MX2012006017A - Indole compound and pharmaceutical use thereof. - Google Patents

Indole compound and pharmaceutical use thereof.

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Publication number
MX2012006017A
MX2012006017A MX2012006017A MX2012006017A MX2012006017A MX 2012006017 A MX2012006017 A MX 2012006017A MX 2012006017 A MX2012006017 A MX 2012006017A MX 2012006017 A MX2012006017 A MX 2012006017A MX 2012006017 A MX2012006017 A MX 2012006017A
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MX
Mexico
Prior art keywords
group
optionally substituted
substituents selected
alkoxy
compound
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Application number
MX2012006017A
Other languages
Spanish (es)
Inventor
Teruhiko Inoue
Shinichi Kikuchi
Munenori Maekawa
Tetsudo Kaya
Koji Matsumura
Ritsuki Masuo
Motoya Suzuki
Original Assignee
Japan Tobacco Inc
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Application filed by Japan Tobacco Inc filed Critical Japan Tobacco Inc
Publication of MX2012006017A publication Critical patent/MX2012006017A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

Disclosed are: a therapeutic or prophylactic agent for inflammatory diseases, allergic diseases and autoimmune diseases; an agent for suppressing rejection in organ transplantation; and the like. Specifically disclosed is a compound represented by general formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof. (In the formula, the symbols are as defined in the description.).

Description

COMPOUNDS OF INDOL AND ITS PHARMACEUTICAL USE TECHNICAL FIELD The present invention relates to an indole compound and a pharmaceutical use thereof. More particularly, the present invention relates to a compound for the prophylaxis or treatment of inflammatory diseases, allergic diseases, autoimmune diseases, rejection of transplantation and the like, by the suppression of functional Th2 cells and / or mast cells by the inhibition of the inducible T cell kinase (ITK), and its use.
ANTECEDENTS OF THE TECHNIQUE ITK is a non-receptor type tyrosine kinase that belongs to the Tec family and is essential for the activation of T cells, and is expressed mainly in T cells, mast cells and natural killer cells. ITK is activated in T cells after stimulation of the T cell receptor (TCR), and is activated in mast cells after activation of the E receptor of high affinity immunoglobulin (Ig). After stimulation of the receptor on T cells, Lck, which is a member of the Src tyrosine kinase family, phosphorylates Y511 in the activation loop of the ITK kinase domain. Activated ITK, together with Zap-70, is necessary for the phosphorylation and activation of PLC- ?. PLC-? it catalyzes the formation of inositol 1, 4,5-trisphosphoric acid and diacylglycerol, which causes calcium mobilization and PKC activation, respectively. These events activate many production pathways, and ultimately cause the production of cytokines in T cells and degranulation in mast cells.
Studies using mice deficient in ITK have confirmed that ITK is involved in the differentiation of Th2 cells.
Th2 cells is a class of CD4 positive helper T cells (Th cells), which differs from inactive T cells by stimulation with the antigen, and produces the cytokine. Cytokines such as interleukin (IL) -4, IL-5, IL-13 and the like are produced by Th2 cells called Th2 cytokine and are known to be involved in the mechanism of allergic disease, and the like, since they promote production of antibodies by cells differentiated from B cells and activate cells such as eosinophils (a class of granulocytes) and the like. Like Th2 cells, Th1 cells that differentiate from inactive T cells produce so-called Th1 cytokines such as interferon (IFN) -y and the like, and Th1 cells and Th2 cells maintain an equilibrium relationship called Th1 balance. Th2 by the suppression of the functions among themselves. An imbalance towards the cytokine is considered to cause specific diseases for each of them. It has been reported that ITK-deficient mice selectively inhibit Th2 cell differentiation and Th2 cytokine production.
In addition, inhibition of ITK inhibits mast cell activation.
Mast cells contain several chemical mediators such as histamine. When an antigen binds to the IgE bound to the cell surface, the established cross-linking triggers cell activation, which consequently causes the release of its content (chemical mediators such as histamine, and the like) (degranulation). Of the chemical mediators released from mast cells, histamine, and the like have a bronchial smooth muscle constriction action, an enhancing effect of blood vessel permeability, a secretory mucous action, and the like and cause asthma and allergic diseases.
Consequently, it is expected that an ITK inhibitor that suppresses Th2 cell proliferation and Th2 cytokine production and / or suppresses degranulation and histamine production, and the like by suppressing mast cell activation shows a effect as an agent for the treatment or prophylaxis of diseases involving the proliferation of Th2 cells, production of Th2 cytokine, degranulation, production of histamine, and the like, for example, inflammatory diseases, allergic diseases and the like.
Recently, it is suggested that ITK is also involved in the activation of Th17 cells, which is a class of Th cells, and it is expected that an ITK inhibitor will show effect as an agent for the treatment or prophylaxis of diseases involving the Th17 cells, such as autoimmune diseases (e.g., rheumatism, and the like).
In addition, it is suggested that ITK is involved in a mixed lymphocyte reaction. Consequently, an ITK inhibitor is expected to show an effect as a rejection inhibitor in a transplant.
In addition, it is suggested that ITK is involved in HIV infection. Therefore, an ITK inhibitor is expected to show an effect as a prophylactic or therapeutic agent of HIV infection.
BRIEF DESCRIPTION OF THE INVENTION Problems to be solved by the invention The present invention has for its object to provide an agent for the treatment or prophylaxis of inflammatory diseases, an agent for the treatment or prophylaxis of allergic diseases, an agent for the treatment or prophylaxis of autoimmune diseases, a rejection inhibitor. in transplantation and the like, which are based on the inhibitory action of ITK.
Means to solve problems The present inventors have conducted intensive studies in an attempt to develop an agent for the treatment or prophylaxis of inflammatory diseases, an agent for the treatment or prophylaxis of allergic diseases, an agent for the treatment or prophylaxis of autoimmune diseases. , an inhibitor of rejection in transplantation and the like, which are based on the inhibitory action of ITK, and found an indole compound having an inhibitory action of ITK, which resulted in the completion of the present invention.
Accordingly, the present invention provides the following. [1] A compound represented by the following formula [I] or a pharmaceutically acceptable salt thereof: where R1 is (1) a hydrogen atom, (2) a hydroxy group, or (3) a Ci_6 alkoxy group optionally substituted with the aryl groups R2 and R3 are the same or different and each one is (1) a hydrogen atom, or (2) a C-i6 alkyl group optionally substituted by 1 to 3 substituents selected from (a) a hydroxy group and (b) a Ci_6 alkoxy group; Y R4 is a group represented by which is attached to position 5 or position 6 of the indole ring, where R5 is (1) a hydrogen atom, or (2) a C ^ alkyl group, and R6 is (1) a hydrogen atom, (2) a C-i_6 alkyl group optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) an alkoxy group C-i-e, (c) a carboxy group, (d) a C 1 -6-carbonyl alkoxy group, (e) an aryl group? ß - ??, (f) an aryl group C6-io-o ¡, (g) an amino group optionally mono- or disubstituted with Ci_6 alkyl groups, (h) a 5 or 6 membered unsaturated heterocyclic group optionally substituted with C-i-s alkyl groups and (i) a saturated 5- or 6-membered heterocyclic group, (3) an alkoxy group C-i_6, (4) a C6-10 aryl group, or (5) a 5 or 6 membered unsaturated heterocyclic group optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group and (b) an alkoxy group Ci_s or R5 and R6 form, together with the nitrogen atom to which they are attached, a cyclic amine of 5 or 6 members (said cyclic amine is optionally condensed with 5 or 6 membered unsaturated heterocycle) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a Ci_6 alkyl group, (c) a Ci_6 alkoxy group and (d) a d6-carbonyl alkoxy group; R7 is (1) a hydrogen atom, or (2) a Ci_6 alkyl group optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) an alkoxy group Ci_6 and (c) an amino group optionally mono- or disubstituted with Ci_s alkyl groups, and R8 is (1) a Ci_6 alkyl group optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) an alkoxy group Ci_e optionally substituted with aryl groups Ce-10, (c) a C3-6 cycloalkyl group optionally substituted with Ci_6 alkoxy groups, (d) an aryl group Ce - ??, (e) a 5 or 6 membered unsaturated heterocyclic group optionally substituted with oxo groups, (f) a saturated 5- to 8-membered heterocyclic group optionally substituted with 1 to 3 substituents selected from (i) a hydroxy group, (ii) an alkyl group optionally substituted with 1 to 3 substituents selected from a hydroxy group and a Ci_6 alkoxy group, (iii) a Ci_6 alkoxy group and (iv) an oxo group, (g) a C3_6-oxy cycloalkyl group, (h) an aryl group C6-io-o i, (i) a 5 or 6 membered unsaturated heterocyclyloxy group, (j) a saturated 5- or 6-membered heterocyclyloxy group and (k) an amino group optionally mono- or disubstituted with substituents selected from (1) a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from a hydroxy group, a carboxy group and a carboxy-C 1-6 alkoxy group, (ii) a Ci_6-carbonyl alkyl group optionally substituted with 1 to 3 substituents selected from a hydroxy group and an Ci_s alkoxy group, (iii) a Ci_6-carbonyl alkoxy group optionally substituted by aryl groups Ce-io, and (iv) a C3_s-carbonyl cycloalkyl group optionally substituted with Ci_6 alkoxy groups, (2) an alkoxy group Ci_s optionally substituted with aryl groups Ce-io, (3) a C3_6 cycloalkyl group optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group and (b) a Ci_6 alkoxy group, (4) a C6-io aryl group optionally substituted with Ci_6 alkyl groups optionally substituted with 1 to 3 halogen atoms, (5) an amino group optionally mono- or disubstituted with Ci_e alkyl groups optionally substituted with Ce-ar aryl groups, (6) an unsaturated 5- or 6-membered heterocyclic group optionally substituted with C1-6 alkyl groups, (7) a 5- or 6-membered saturated heterocyclic group optionally substituted with 1 to 3 substituents selected from (a) a Ci_6 alkyl group, (b) a Ci_6-carbonyl alkyl group and (c) an oxo group, (8) a C3-6-OXI cycloalkyl group, or (9) an aryl Ce-1-carbonyl group or R7 and R8 form, together with the nitrogen atom and the carbon atom to which they are attached, a cyclic amine of 5 or 6 members substituted with an oxo group and also optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a C-i_6 alkyl group optionally substituted with hydroxy groups, (c) a C 1-6 alkoxy group and (d) a C3_6 cycloalkyl group. [2] A compound represented by the following formula [1-a] or a pharmaceutically acceptable salt thereof: where R1 is (1) a hydrogen atom, (2) a hydroxy group, or (3) a C-i-s alkoxy group optionally substituted with C6-io aryl groups R2 and R3 are the same or different and each one is (1) a hydrogen atom, or (2) an alkyl group optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group and (b) a Ci_6 alkoxy group; R7 'is an alkyl group Ci_e optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) an alkoxy group Ci_6 and (c) an amino group optionally mono- or disubstituted with Ci_6 alkyl groups, and R8 is (1) a Ci_6 alkyl group optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a Ci_6 alkoxy group optionally substituted with Ce-10 aryl groups, (c) a C3-6 cycloalkyl group optionally substituted with Ci_6 alkoxy groups, (d) a C6-10 aryl group, (e) a 5 or 6 membered unsaturated heterocyclic group optionally substituted with oxo groups, (f) a saturated 5- to 8-membered heterocyclic group optionally substituted with 1 to 3 substituents selected from (i) a hydroxy group, (ii) a C-i_6 alkyl group optionally substituted with 1 to 3 substituents selected from a hydroxy group and a Ci_6 alkoxy group, (iii) an alkoxy group Ci_e and (iv) an oxo group, (g) a C3_s-oxy cycloalkyl group, (h) an aryl Ce-io-oxy group, (i) a 5 or 6 membered unsaturated heterocyclyloxy group, 0) a saturated 5- or 6-membered heterocyclyloxy group and (k) an amino group optionally mono- or disubstituted with substituents selected from (1) a Ci_6 alkyl group optionally substituted with 1 to 3 substituents selected from a hydroxy group, a carboxy group and a carboxy-alkoxy group Ci_6, (ii) an alkyl Ci-s-carbonyl group optionally substituted with 1 to 3 substituents selected from a hydroxy group and a Ci_6 alkoxy group, (iii) a Ci_6-carbonyl alkoxy group optionally substituted with C6_io aryl groups and (iv) a C3_s-carbonyl cycloalkyl group optionally substituted with C ^ alkoxy groups, (2) a C 1 alkoxy group optionally substituted with C 6 -io aryl groups. (3) a C3_6 cycloalkyl group optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group and (b) an alkoxy group C-i_6, (4) a C6-10 aryl group optionally substituted with Ci_6 alkyl groups optionally substituted with 1 to 3 halogen atoms, (5) an amino group optionally mono- or disubstituted with Ci_s alkyl groups optionally substituted with aryl? -β-? (6) a 5- or 6-membered unsaturated heterocyclic group optionally substituted with Ci_s alkyl groups, (7) a saturated 5- or 6-membered heterocyclic group optionally substituted with 1 to 3 substituents selected from (a) a Ci_6 alkyl group, (b) an alkyl Ci-6-carbonyl group and (c) an oxo group, (8) a C3_6-oxy cycloalkyl group, or (9) an aryl C6-io-carbonyl group or R7 and R8 form, together with the nitrogen atom and the carbon atom to which they are attached, a cyclic amine of 5 or 6 members substituted with an oxo group and also optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) an alkyl group Ci_e optionally substituted with hydroxy groups, (c) an alkoxy group C-i_6 and (d) a C3-6 cycloalkyl group. [3] The compound according to the point [2] mentioned above, wherein R1 is a hydrogen atom; Y they are the same or different and each one is an alkyl group '1-6, or one of its pharmaceutically acceptable salts. [4] The compound according to the point [3] mentioned above, wherein R7 is a Ci ^ alkyl group; Y R8 is a C-i-6 alkyl group substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) an alkoxy group Ci_e optionally substituted with aryl groups Ce-10, (c) a C3-6 cycloalkyl group optionally substituted with Ci_6 alkoxy groups, (d) an aryl group C &-. 10, (e) a 5 or 6 membered unsaturated heterocyclic group optionally substituted with oxo groups, (f) a saturated 5- to 8-membered heterocyclic group optionally substituted with 1 to 3 substituents selected from (i) a hydroxy group, (ii) an Ci_e alkyl group optionally substituted with 1 to 3 substituents selected from a hydroxy group and a Ci_6 alkoxy group, (iii) a C 1-6 alkoxy group and (iv) an oxo group, (g) a cycloalkyl group Ca-e-oxy, (h) an aryl C6-io-oxy group, (i) a 5 or 6 membered unsaturated heterocyclyloxy group, (j) a saturated 5- or 6-membered heterocyclyloxy group and (k) an amino group optionally mono- or disubstituted with substituents selected from (i) a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from a hydroxy group, a carboxy group and a carboxy-C 1-6 alkoxy group, (ii) a Ci_6-carbonyl alkyl group optionally substituted with 1 to 3 substituents selected from a hydroxy group and a Ci_6 alkoxy group, (iii) a Ci-6-carbonyl alkoxy group optionally substituted with aryl groups Ce-io and (iv) a C3-6-carbonyl cycloalkyl group optionally substituted with Ci_6 alkoxy groups, or one of its pharmaceutically acceptable salts. [5] A compound selected from the following formulas ?? ?? or one of its pharmaceutically acceptable salts. [6] A pharmaceutical composition comprising the compound according to any of the items [1] to [5] mentioned above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. [7] An ITK inhibitor comprising the compound according to any of the aforementioned points [1] to [5] or a pharmaceutically acceptable salt thereof. [8] An agent for the treatment or prevention of an inflammatory disease, comprising the compound according to any of the items [1] to [5] mentioned above or a pharmaceutically acceptable salt thereof. [9] The agent according to item [8] mentioned above, wherein the inflammatory disease is rheumatoid arthritis. [10] An agent for the treatment or prevention of an allergic disease, comprising the compound according to any of the items [1] to [5] mentioned above or a pharmaceutically acceptable salt thereof. [11] An agent for the treatment or prevention of an autoimmune disease, comprising the compound according to any of the items [1] to [5] mentioned above or a pharmaceutically acceptable salt thereof. [12] The agent according to item [1 1] mentioned above, wherein the autoimmune disease is rheumatoid arthritis. [13] An inhibitor of rejection to transplantation, comprising the compound according to any of the items [1] to [5] mentioned above or a pharmaceutically acceptable salt thereof. [14] A method of inhibiting ITK in a mammal, comprising administering a pharmaceutically effective amount of the compound according to any of the above-mentioned [1] to [5] or one of its pharmaceutically acceptable salts, to the mammal . [15] A method of treating or preventing an inflammatory disease in a mammal, comprising administering a pharmaceutically effective amount of the compound according to any of the above [1] to [5] or a pharmaceutically acceptable salt thereof acceptable, to the mammal. [16] The method according to the item [15] mentioned above, wherein the inflammatory disease is rheumatoid arthritis. [17] A method of treating or preventing an allergic disease in a mammal, comprising administering a pharmaceutically effective amount of the compound according to any of the above [1] to [5] or a pharmaceutically acceptable salt thereof acceptable, to the mammal. [18] A method of treating or preventing an autoimmune disease in a mammal, comprising administering a pharmaceutically effective amount of the compound according to any of the above [1] to [5] or a pharmaceutically acceptable salt thereof acceptable, to the mammal. [19] The method according to item [18] mentioned above, wherein the autoimmune disease is rheumatoid arthritis. [20] A method of suppressing rejection to transplantation in a mammal, comprising administering a pharmaceutically effective amount of the compound according to any of the above [1] to [5] or a pharmaceutically acceptable salt thereof, to the mammal. [21] Use of the compound according to any of the above [1] to [5] or a pharmaceutically acceptable salt thereof, to produce an agent for the treatment or prevention of an inflammatory disease. [22] Use according to the item [21] mentioned above, wherein the inflammatory disease is rheumatoid arthritis. [23] Use of the compound according to any of the points [1] to [5] mentioned above or a pharmaceutically acceptable salt thereof, to produce an agent for the treatment or prevention of an allergic disease. [24] Use of the compound according to any of the items [1] to [5] mentioned above or a pharmaceutically acceptable salt thereof, to produce an agent for the treatment or prevention of an autoimmune disease. [25] Use according to the item [24] mentioned above, wherein the autoimmune disease is rheumatoid arthritis. [26] Use of the compound according to any of the items [1] to [5] mentioned above or a pharmaceutically acceptable salt thereof, to produce a rejection inhibitor to transplantation. [27] A commercial kit comprising (a) a pharmaceutical composition comprising the compound according to any of the above [1] to [5] or a pharmaceutically acceptable salt thereof as an active ingredient and (b) a written description associated therewith, which states that the pharmaceutical composition can or should be used to treat or prevent an inflammatory disease, an allergic disease or an autoimmune disease. [28] A commercial package comprising (a) a pharmaceutical composition comprising the compound according to any of the above [1] to [5] or a pharmaceutically acceptable salt thereof as an active ingredient and (b) a written description associated therewith, which states that the pharmaceutical composition can or should be used to treat or prevent an inflammatory disease, an allergic disease or an autoimmune disease.
A compound represented by the following formula [] or a pharmaceutically acceptable salt thereof or one of its solvates: where R1 'is (1) a hydrogen atom, (2) a hydroxy group, or (3) a C-i_6 alkoxy group optionally substituted with aryl groups Ce-;; R2 and R3 are the same or different and each one is (1) a hydrogen atom, or (2) an alkyl group optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group and (b) a Ci-β alkoxy group; Y R4 is a group represented by which is attached to position 5 or position 6 of the indole ring, where R5 'is (1) a hydrogen atom, or (2) a C-i_6 alkyl group, and R6 'is (1) a hydrogen atom, (2) a C-i_6 alkyl group optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a C ^ alkoxy group, (c) a carboxy group, (d) a Ci_6-carbonyl alkoxy group, (e) an aryl C & (f) an aryl group C6-io-ox, (g) an amino group optionally mono- or disubstituted with Ci_6 alkyl groups, (h) a 5 or 6 membered unsaturated heterocyclic group optionally substituted with C-i_6 alkyl groups and (i) a saturated 5- or 6-membered heterocyclic group, (3) a Ci_6 alkoxy group, (4) a C6-10 aryl group, or (5) a 5 or 6 membered unsaturated heterocyclic group optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group and (b) a Ci_6 alkoxy group or R5 and R6 form, together with the nitrogen atom to which they are attached, a cyclic amine of 5 or 6 members (said cyclic amine is optionally condensed with 5 or 6 membered unsaturated heterocycle), which is optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a Ci_6 alkyl group, (c) a Ci_6 alkoxy group and (d) a Ci_6-carbonyl alkoxy group; R7"is (1) a hydrogen atom, or (2) a C-i_6 alkyl group optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) an alkoxy group C-i_6 and (c) an amino group optionally mono- or disubstituted with Ci_6 alkyl groups, and R8 'is (1) a C-i_6 alkyl group optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) an alkoxy group C-i_e optionally substituted with aryl groups Ce-io, (c) a C 3-6 cycloalkyl group optionally substituted with C 1-6 alkoxy groups, (d) an aryl group? ß - ??, (e) a 5 or 6 membered unsaturated heterocyclic group optionally substituted with oxo groups, (f) a saturated 5- to 8-membered heterocyclic group optionally substituted with 1 to 3 substituents selected from (i) a hydroxy group, (ii) a C-i-g alkyl group optionally substituted with 1 to 3 substituents selected from a hydroxy group and an alkoxy group Ci_e, (iii) a C 1-6 alkoxy group and (iv) an oxo group, (g) a C3_6-oxy cycloalkyl group, (h) an aryl C6-io-oxi group, (i) a 5 or 6 membered unsaturated heterocyclyloxy group, (j) a saturated 5- or 6-membered heterocyclyloxy group and (k) an amino group optionally mono- or disubstituted with substituents selected from (i) a C1-6 alkyl group, (ii) a Ci_6-carbonyl alkyl group optionally substituted with 1 to 3 substituents selected from a hydroxy group and a C 1 alkoxy group, (ii) a C 1 -carbonyl alkoxy group optionally substituted with aryl groups Ce-? Y (iv) a C3_6-carbonyl cycloalkyl group optionally substituted with C-i_6 alkoxy groups, (2) an alkoxy group Ci_e optionally substituted with C5-10 aryl groups, (3) a C3_6 cycloalkyl group optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group and (b) a Ci_6 alkoxy group, (4) a C6-io aryl group optionally substituted with alkyl groups optionally substituted with 1 to 3 halogen atoms, (5) an amino group optionally mono- or disubstituted with C-1 alkyl groups optionally substituted with C5-.10 aryl groups, (6) a 5 or 6 membered unsaturated heterocyclic group optionally substituted with Ci_e alkyl groups, (7) a 5- or 6-membered saturated heterocyclic group optionally substituted with 1 to 3 substituents selected from (a) a Ci_6 alkyl group, (b) a Ci_6-carbonyl alkyl group and (c) an oxo group, (8) a C3_6-oxy cycloalkyl group, or (9) an aryl C6-io-carbonyl group or R7 and R8 form, together with the nitrogen atom and the carbon atom to which they are attached, a cyclic amine of 5 or 6 members substituted with an oxo group and also optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) an alkyl group optionally substituted with hydroxy groups, (c) a Ci_6 alkoxy group and (d) a C3-6 cycloalkyl group. [2] A compound represented by the following formula [G-a] or a pharmaceutically acceptable salt thereof or one of its solvates: where R 'is (1) a hydrogen atom, (2) a hydroxy group, or (3) a C-i_6 alkoxy group optionally substituted with C6-io aryl groups; R2 and R3 are the same or different and each one is (1) a hydrogen atom, or (2) a Ci_6 alkyl group optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group and (b) a C-i-e alkoxy group; R7 is a Ci_s alkyl group optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) an alkoxy group C-i_6 and (c) an amino group optionally mono- or disubstituted with Ci_6 alkyl groups, and R8 'is (1) a Ci_6 alkyl group optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a Ci_6 alkoxy group optionally substituted with Ce-10 aryl groups, (c) a C3_6 cycloalkyl group optionally substituted with Ci_6 alkoxy groups, (d) a C6-io aryl group > (e) a 5 or 6 membered unsaturated heterocyclic group optionally substituted with oxo groups, (f) a saturated 5- to 8-membered heterocyclic group optionally substituted with 1 to 3 substituents selected from (i) a hydroxy group (ii) a Ci_6 alkyl group optionally substituted with 1 to 3 substituents selected from a hydroxy group and a C-i alkoxy group (iii) a Ci_6 alkoxy group and (iv) an oxo group (g) a C3-6-OXY cycloalkyl group, (h) an aryl C6-io-oxy group, (i) a 5 or 6 membered unsaturated heterocyclyloxy group, (j) a saturated 5- or 6-membered heterocyclyloxy group and (k) an amino group optionally mono- or disubstituted with substituents selected from (i) a Ci_6 alkyl group, (ii) an alkyl C-i-e-carbonyl group optionally substituted with 1 to 3 substituents selected from a hydroxy group and a d6 alkoxy group, (iii) a Ci_6-carbonyl alkoxy group optionally substituted with aryl groups Ce-io and (iv) a C3_6-carbonyl cycloalkyl group optionally substituted with C1-6 alkoxy groups, (2) an alkoxy group Ci_s optionally substituted with aryl groups Ce-io, (3) a C3-6 cycloalkyl group optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group and (b) a Ci_6 alkoxy group, (4) a C6-io aryl group optionally substituted with Ci_6 alkyl groups optionally substituted with 1 to 3 halogen atoms, (5) an amino group optionally mono- or disubstituted with Ci_s alkyl groups optionally substituted with Ce-io aryl groups, (6) a 5- or 6-membered unsaturated heterocyclic group optionally substituted with Ci_s alkyl groups, (7) a 5- or 6-membered saturated heterocyclic group optionally substituted with 1 to 3 substituents selected from (a) a Ci_6 alkyl group, (b) an alkyl Ci -s-carbonyl group and (c) an oxo group, (8) a C3_6-oxy cycloalkyl group, or (9) an aryl C ^ o -carbonyl group or R7 and R8 form, together with the nitrogen atom and the carbon atom to which they are attached, a cyclic amine of 5 or 6 members substituted with an oxo group and also optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a C-i_6 alkyl group optionally substituted with hydroxy groups, (c) a Ci_6 alkoxy group and (d) a C3_6 cycloalkyl group. [3 '] A pharmaceutical composition comprising the compound according to the above [V] or [2'] points or one of its pharmaceutically acceptable salts or one of its solvates and a pharmaceutically acceptable carrier. [4 '] An agent for the treatment or prevention of an inflammatory disease, comprising the compound according to the above-mentioned [Y] or [2'] points or a pharmaceutically acceptable salt thereof or one of its solvates. [5 '] An ITK inhibitor comprising the compound according to the aforementioned points [V] or [2'] or a pharmaceutically acceptable salt thereof or one of its solvates. [6 '] An agent for the treatment or prevention of an allergic disease, comprising the compound according to the items [1'] or [2 '] mentioned above or one of its pharmaceutically acceptable salts or one of its solvates. [7 '] An agent for the treatment or prevention of an autoimmune disease, comprising the compound according to the items [1'] or [2 '] mentioned above or one of its pharmaceutically acceptable salts or one of its solvates. [8 '] An inhibitor of transplant rejection, comprising the compound according to the aforementioned points [1'] or [2 '] or a pharmaceutically acceptable salt thereof or one of its solvates. [9 '] A method of treating or preventing an inflammatory disease in a mammal, comprising administering a pharmaceutically effective amount of the compound according to the above [V] or [2'] points or a pharmaceutically acceptable salt thereof acceptable or one of its solvates to the mammal. [10 '] A method of treating or preventing an allergic disease in a mammal, comprising administering a pharmaceutically effective amount of the compound according to the above-mentioned [Y] or [2'] or a pharmaceutically acceptable salt thereof acceptable or one of its solvates to the mammal. [11 '] A method of treating or preventing an autoimmune disease in a mammal, comprising administering a pharmaceutically effective amount of the compound according to the aforementioned points [1'] or [2 '] or one of its salts pharmaceutically acceptable or one of its solvates to the mammal. [12 '] A method of suppressing transplant rejection in a mammal, comprising administering a pharmaceutically effective amount of the compound according to the aforementioned points [1'] or [2 '] or a pharmaceutically acceptable salt thereof. or one of its solvates, to the mammal. [13 '] Use of the compound according to the above [1'] or [2 '] points or one of its pharmaceutically acceptable salts or one of its solvates to produce an agent for the treatment or prevention of an inflammatory disease.
Effect of the invention The indole compound of the present invention effectively inhibits ITK activity, suppresses proliferation and activation of Th2 cells and / or suppresses mast cell activation. Accordingly, it is effective as an agent for the treatment or prevention of diseases including the proliferation or activation of Th2 cells or the activation of mast cells, for example, allergic diseases, inflammatory diseases and autoimmune diseases or as an inhibitor of rejection of transplant.
DETAILED DESCRIPTION OF THE MODALITIES The present invention is explained in detail below.
The definition of the term used in the present specification is as follows.
The term "optionally substituted" includes both substitution and no substitution (no substitution) in a substitutable position of an object group. Here, "non-substitution" implies that all substitutable positions of an object group are each a hydrogen atom.
Examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
The "Ci_6 alkyl group" implies a saturated straight-chain or branched-chain hydrocarbon group having 1 to 6 carbon atoms and their examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a 1,2-dimethylpropyl group, a 1-ethylpropyl group, a hexyl group, an isohexyl group, a 1,2-trimethylpropyl group, a 1, 1- dimethylbutyl group, a 2,2-dimethylbutyl group, a 3,3-dimethylbutyl group, a 2-ethylbutyl group, and the like.
The "alkoxy group Ci" implies a hydroxyl group substituted with the "alkyl group te" mentioned above and its examples include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec group -butoxy, a tert-butoxy group, a pentyloxy group, an isopentyloxy group, a neopentyloxy group, a 1,2-dimethylpropyloxy group, a 1-ethylpropyloxy group, a hexyloxy group, an isohexyloxy group, a 1, 2,2 group -trimethylpropyloxy, a 1,1-dimethylbutyloxy group, a 2,2-dimethylbutyloxy group, a 3,3-dimethylbutyloxy group, a 2-ethylbutyloxy group, and the like.
The "C3_6 cycloalkyl group" implies a saturated monocyclic hydrocarbon group having 3 to 6 carbon atoms and their examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and the like.
The "C3-6-OXY cycloalkyl group" implies a hydroxy group substituted with the aforementioned "C3_6 cycloalkyl group" and their examples include a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, and the like.
The "aryl group Ce-io" implies an aromatic hydrocarbon group having 6 to 10 carbon atoms and their examples include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, and the like. Preferably, it is a phenyl group.
The "aryl group C6-io-oxy" implies a hydroxy group substituted with the "aryl group C-e-io" mentioned above and its examples include a phenoxy group, a 1-naphthyloxy group, a 2-naphthyloxy group, and the like. A phenoxy group is preferred.
The "5 or 6 membered unsaturated heterocyclic group" means an unsaturated or partially unsaturated monocyclic heterocyclic group having 5 or 6 ring constituent atoms, containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. When the group contains a sulfur atom as a heteroatom, the sulfur atom is optionally mono- or dioxidized. Examples of such a group include a furyl group, a thienyl group, a pyrrolyl group, an oxazolyl group, an oxazolinyl group, an isoxazolyl group, an isoxazolinyl group, a thiazolyl group, a thiazolyl group, an isothiazolyl group, an isothiazolinyl group, an imidazolyl group, an imidazolinyl group, a pyrazolyl group, a pyrazolinyl group, an oxadiazolyl group (a group 1, 2,5-oxadiazolyl, a group 1, 3,4-oxadiazolyl, a 1,2,4-oxadiazolyl group) , a thiadiazolyl group (a 1, 2,5-thiadiazolyl group, a 1,3,4-thiadiazolyl group, a 1, 2,4-thiadiazolyl group), a triazolyl group (a 1, 2,3-triazolyl group, a 1,2-triazolyl group), a tetrazolyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a pyrazinyl group, a triazinyl group, a dihydropyridyl group, and the like.
The "5 or 6 membered unsaturated heterocyclyloxy group" implies a hydroxy group substituted with the above-mentioned "5 or 6 membered unsaturated heterocyclic group" and its examples include a furyloxy group, a thienyloxy group, a pyrrolyloxy group, an oxazolyloxy group, an oxazolinyloxy group, an isoxazolyloxy group, an isoxazolinyloxy group, a thiazolyloxy group, a thiazolinyloxy group, an isothiazolyloxy group, an isothiazolinyloxy group, an imidazolyloxy group, an imidazolinyloxy group, a pyrazolyloxy group, a pyrazolinyloxy group, an oxadiazolyloxy group (a group 1,2,5-oxadiazolyloxy, a group 1, 3,4-oxadiazolyloxy, a group 1, 2,4-oxadiazolyloxy), a thiadiazolyloxy group (a group 1, 2,5-thiadiazolyloxy, a group 1, 3,4 Thiadiazolyloxy, a 1,2-thiadiazolyloxy group), a triazolyloxy group (a 1,2,3-triazolyloxy group, a 1, 2,4-triazolyloxy group), a tetrazolyloxy group, a pyridyloxy group, a pyrimidinyloxy group , a pyridazinyloxy group, a pyrazinyloxy group, a triazinyloxy group, a dihydropyridyloxy group, and the like.
The "5- to 8-membered saturated heterocyclic group" implies a monocyclic saturated heterocyclic group having 5 to 8 ring constituent atoms, containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, an atom of oxygen and a sulfur atom. When the group contains a sulfur atom as a heteroatom, the sulfur atom is optionally mono- or dioxidized. Examples of such a group include a pyrrolidinyl group, a tetrahydrofuryl group, a tetrahydropyranyl group, a tetrahydrothienyl group, a group tetrahydrothiopyranyl, an oxazolidinyl group, an isoxazolidinyl group, a thiazolidinyl group, an isothiazolidinyl group, an imidazolidinyl group, a pyrazolidinyl group, a piperidyl group (including a piperidino group), a morpholinyl group (including a morpholino group), a thiomorpholinyl group (including a thiomorpholino group), a piperazinyl group, an azepanyl group, an azocanyl group, a 1,1-dioxideisothiazolidinyl group, a 1,1-dioxidetetrahydrothienyl group, a 1, 1-dioxidetetrahydrothiopyranyl group, a 1, 1-dioxidethiomorpholinyl group (including a 1, 1-dioxidethiomorpholino group) and the like.
The "5- or 6-membered saturated heterocyclic group" means, among the "5- to 8-membered saturated heterocyclic groups" mentioned above, a group having 5 or 6 ring constituents and their examples include a pyrrolidinyl group, a tetrahydrothiopyranyl group, a tetrahydropyranyl group, a tetrahydrothienyl group, a tetrahydrothiopyranyl group, an oxazolidinyl group, an isoxazolidinyl group, a thiazolidinyl group, an isothiazolidinyl group, an imidazolidinyl group, a pyrazolidinyl group, a piperidyl group (including a piperidino group), a morpholinyl group (including a morpholino group), a thiomorpholinyl group (including a thiomorpholino group), a piperazinyl group, a 1, 1-dioxideisothiazolidinyl group, a 1, 1-dioxidetetrahydrothienyl group, a 1, 1 group -dioxidetetrahydrothiopyranyl, a 1, 1-dioxidethiomorpholinyl group (including group 1, 1-dioxidethiomorpholino) and the like.
The "saturated 5- or 6-membered heterocyclyloxy group" implies a hydroxy group substituted with the above-mentioned "5- or 6-membered saturated heterocyclic group" and their examples include a pyrrolidinyloxy group, a tetrahydrofuryloxy group, a tetrahydropyranyloxy group, a tetrahydrothienyloxy group, a tetrahydrothiopyranyloxy group, an oxazolidinyloxy group, an isoxazolidinyloxy group, a thiazolidinyloxy group, an isothiazolidinyloxy group, an imidazolidinyloxy group, a pyrazolidinyloxy group, a piperidyloxy group (including a piperidinoxy group), a morpholinyloxy group (including a morpholinoxy group), a thiomorpholinyloxy group (including a thiomorpholinoxy group), a piperazinyloxy group, a group 1, 1-dioxideisothiazolidinyloxy, a group 1, 1-dioxidetetrahydrothienyloxy, a 1, 1-dioxidetetrahydrothiopyranyloxy group, a group 1, -diioxythiomorpholinyloxy (including a group 1, -dioxidethiomorpholinoxy) and the like.
The "Ci_6-carbonyl alkyl group" implies a carbonyl group to which the above-mentioned "Ci_6 alkyl group" is attached and its examples include an acetyl group, a propanoyl group, a butanoyl group, a 2-methylpropanoyl group, a group 2, 2-dimethylpropanoyl, a 3-methylbutanoyl group, and the like.
The "C 1 -carbonyl alkoxy group" implies a carbonyl group to which the above-mentioned "C 1-6 alkoxy group" is attached and its examples include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group , an isobutoxycarbonyl group, a sec-butoxycarbonyl group, a tert-butoxycarbonyl group, a pentyloxycarbonyl group, an isopentyloxycarbonyl group, a neopentyloxycarbonyl group, a hexyloxycarbonyl group, and the like.
The "cycloalkyl C ^ -carbonyl group" implies a carbonyl group to which the above-mentioned "C3_6 cycloalkyl group" is attached and its examples include a cyclopropylcarbonyl group, a cyclobutylcarbonyl group, a cyclopentylcarbonyl group, a cyclohexylcarbonyl group, and the like.
The "aryl C6-io-carbonyl group" implies a carbonyl group to which the aforementioned "aryl group Ce-io" is attached and its examples include a benzoyl group, and the like.
The "carboxy-alkoxy group C i 'implies the above-mentioned group" Ci_6 alkoxy group "to which a carboxy group is attached and their examples include a carboxymethoxy group, a 2-carboxyethoxy group, a 3-carboxypropoxy group, a 2- group carboxy-1-methylethoxy, a 4-carboxybutoxy group, and the like A carboxymethoxy group is preferred.
The "5 or 6 membered cyclic amine" implies a saturated heterocycle having 5 or 6 ring constituents, containing at least one nitrogen atom in addition to carbon atoms, which also optionally contains 1 to 3 heteroatoms selected from an atom of nitrogen, an oxygen atom and a sulfur atom, which is attached through the nitrogen atom constituent of the ring. When the ring contains a sulfur atom as a heteroatom, the sulfur atom is optionally mono- or dioxidized. Examples of such a ring include pyrrolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, imidazolidine, pyrazolidine, piperidine, morpholine, thiomorpholine, piperazine, 1, 1- dioxideisothiazolidine, 1, 1-dioxidethiomorpholine, and the like.
The "5 or 6 membered unsaturated heterocycle" implies a monocyclic unsaturated or partially unsaturated heterocyclic group having 5 or 6 ring constituent atoms, containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, oxygen atom and a sulfur atom. When the ring contains a sulfur atom as a heteroatom, the sulfur atom is optionally mono- or dioxidized. Examples of such ring include furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, siathiazole, imidazole, pyrazole, oxadiazole, thiadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, and the like.
Each group of a compound represented by the formula [I] (hereinafter, sometimes abbreviated as compound [I]) is explained below.
R1 is (1) a hydrogen atom, (2) a hydroxy group, or (3) an alkoxy group (preferably a methoxy group, an isopropoxy group) optionally substituted with aryl groups Ce- ?? (preferably, a phenyl group), and, preferably, a hydrogen atom.
R2 and R3 are the same or different and each one is (1) a hydrogen atom, or (2) a C ^ alkyl group (preferably a methyl group) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group and (b) a C-i_6 alkoxy group (preferably a methoxy group) and preferably are the same or different and each is a C-i_6 alkyl group (preferably a methyl group).
R4 is a group represented by which is attached to position 5 or position 6 of the indole ring.
R4 is preferably which is attached to position 5 or position 6 of the indole ring or which is attached to position 6 of the indole ring and more preferably which is attached to position 6 of the indole ring.
R5 is (1) a hydrogen atom, or (2) a C-i_6 alkyl group (preferably, a methyl group, an ethyl group).
R6 is (1) a hydrogen atom, (2) a Ci_s alkyl group (preferably a methyl group, an ethyl group, an isopropyl group, an isobutyl group, a tert-butyl group, a neopentyl group, a 1, 2-dimethylpropyl group, a 1, 2 group , 2-trimethylpropyl) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) an alkoxy group Ci_e (preferably, a methoxy group, a propoxy group, an isopropoxy group), (c) a carboxy group, (d) a Ci_6-carbonyl alkoxy group (preferably a methoxycarbonyl group, a tert-butoxycarbonyl group), (e) an aryl group Ce- ?? (preferably, a phenyl group), (f) an aryl group C6-io-o i (preferably a phenoxy group), (g) an amino group optionally mono- or disubstituted with C-i_6 alkyl groups (preferably a methyl group), (h) a 5 or 6 membered unsaturated heterocyclic group (preferably, a furyl group, a pyrrolyl group, a thiazolyl group, a tetrazolyl group, an imidazolyl group) optionally substituted with Ci_6 alkyl groups (preferably a methyl group) Y (i) a saturated 5- or 6-membered heterocyclic group (preferably a morpholinyl group), (3) a C1_s alkoxy group (preferably a methoxy group), (4) an aryl group Ce-io (preferably, a phenyl group), or (5) a 5 or 6 membered unsaturated heterocyclic group (preferably, a 1,3-thiadiazolyl group) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group and (b) a Ci_6 alkoxy group (preferably, a methoxy group).
Alternatively, R5 and R6 can form, together with the nitrogen atom to which they are attached, a cyclic amine of 5 or 6 members (preferably, pyrrolidine, piperidine, piperazine, morpholine) (the cyclic amine is optionally condensed with a 5 or 6 membered unsaturated heterocycle (preferably imidazole)), which is optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a Ci_6 alkyl group (preferably, a methyl group, a ethyl group), (c) a Ci_6 alkoxy group (preferably a methoxy group) and (d) an alkoxy Ci-e-carbonyl group (preferably, a tert-butoxycarbonyl group).
R7 is (1) a hydrogen atom, or (2) a Ci_6 alkyl group (preferably, a methyl group, an ethyl group, a propyl group) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a Ci_6 alkoxy group (preferably a methoxy group) and (c) an amino group optionally mono- or disubstituted with Ci_e alkyl groups (preferably a methyl group), preferably a Ci_6 alkyl group (preferably, a methyl group, an ethyl group, a propyl group) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a Ci_6 alkoxy group (preferably a methoxy group) and (c) an amino group optionally mono- or disubstituted with Ci_e alkyl groups (preferably a methyl group), and, more preferably, a Ci_6 alkyl group (preferably, a methyl group, an ethyl group, a propyl group).
R8 is (1) a Ci_6 alkyl group (preferably, a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a tert-butyl group, a neopentyl group) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a Ci_6 alkoxy group (preferably, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group) optionally substituted with C-6-10 aryl groups (preferably, a phenyl group), (c) a C3-6 cycloalkyl group (preferably, a cyclopentyl group, a cyclohexyl group) optionally substituted with alkoxy groups Ci_6 (preferably a methoxy group), (d) an aryl group Ce- ?? (preferably, a phenyl group), (e) a 5 or 6 membered unsaturated heterocyclic group (preferably, an imidazolyl group, a dihydropyridyl group, a pyrazolyl group) optionally substituted with oxo groups, (f) a saturated 5- to 8-membered heterocyclic group (preferably, a tetrahydrofuryl group, a tetrahydropyranyl group, a pyrrolidinyl group, a piperidyl group, an azepanyl group, an azocanyl group, a morpholinyl group (including a morpholino group), a 1, 1-dioxideisothiazolidinyl group, an oxazolidinyl group, an imidazolidinyl group) optionally substituted with 1 to 3 substituents selected from (i) a hydroxy group, (ii) a Ci_6 alkyl group (preferably a methyl group) optionally substituted with 1 to 3 substituents selected from a hydroxy group and a C-i_6 alkoxy group (preferably a methoxy group), (iii) a Ci_6 alkoxy group (preferably a methoxy group) and (iv) an oxo group, (g) a C3_s-oxy cycloalkyl group (preferably a cyclopentyloxy group), (h) an aryl Ce-io-oxy group (preferably a phenoxy group), (i) a 5 or 6 membered unsaturated heterocyclyloxy group (preferably a pyridyloxy group), (j) a saturated 5- or 6-membered heterocyclyloxy group (preferably, a tetrahydrofuryloxy group, a tetrahydropyranyloxy group) and (k) an amino group optionally mono- or disubstituted with substituents selected from (i) a Ci_6 alkyl group (preferably a methyl group) optionally substituted with 1 to 3 substituents selected from a hydroxy group, a carboxy group and a Ci_6 carboxy-alkoxy group (preferably a carboxymethoxy group), (ii) a Ci_6-carbonyl alkyl group (preferably, an acetyl group, a propanoyl group, a 2-methylpropanoyl group, a 2,2-dimethylpropanoyl group, a 3-methylbutanoyl group) optionally substituted with 1 to 3 substituents selected from a hydroxy group and an alkoxy group Ci_e (preferably a methoxy group), (iii) a Ci_6-carbonyl alkoxy group (preferably a methoxycarbonyl group, a tert-butoxycarbonyl group) optionally substituted with aryl groups Ce- ?? (preferably, a phenyl group) and (iv) a C3_s-carbonyl cycloalkyl group (preferably, a cyclopropylcarbonyl group, a cyclohexylcarbonyl group) optionally substituted with Ci_6 alkoxy groups (preferably a methoxy group), (2) a Ci_6 alkoxy group (preferably a methoxy group) optionally substituted with aryl groups Ce- ?? (preferably, a phenyl group), (3) a cycloalkyl group (preferably, a cyclopentyl group, a cyclohexyl group) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group and (b) an alkoxy group C-i_6 (preferably a methoxy group), (4) an aryl group? E- ?? (preferably, a phenyl group) optionally substituted with C 1-6 alkyl groups (preferably a methyl group) optionally substituted with 1 to 3 halogen atoms (preferably, a fluorine atom), (5) an amino group optionally mono- or disubstituted with Ci_6 alkyl groups (preferably, a methyl group) optionally substituted with aryl groups? T- ?? (preferably, a phenyl group), (6) a 5 or 6 membered unsaturated heterocyclic group (preferably, an isoxazolyl group) optionally substituted with C-i-6 alkyl groups (preferably a methyl group), (7) a saturated 5- or 6-membered heterocyclic group (preferably, a tetrahydrofuryl group, a tetrahydropyranyl group, a pyrrolidinyl group, a piperidyl group) optionally substituted with 1 to 3 substituents selected from (a) a Ci_6 alkyl group (preferably a methyl group), (b) an alkyl C-i-6-carbonyl group (preferably an acetyl group) and (c) an oxo group, (8) a cycloalkyl group Ca-e-oxy (preferably a cyclohexyloxy group), or (9) an aryl C6-io-carbonyl group (preferably, a benzoyl group).
R8 is preferably a Ci_e alkyl group (preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a tert-butyl group, a neopentyl group) substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a Ci_6 alkoxy group (preferably, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group) optionally substituted with C6_-io aryl groups (preferably, a phenyl group), (c) a C3_6 cycloalkyl group (preferably, a cyclopentyl group, a cyclohexyl group) optionally substituted with C-i6 alkoxy groups (preferably a methoxy group), (d) an aryl group C & -10 (preferably, a phenyl group), (e) a 5 or 6 membered unsaturated heterocyclic group (preferably, an imidazolyl group, a dihydropyridyl group, a pyrazolyl group) optionally substituted with oxo groups, (f) a saturated 5- to 8-membered heterocyclic group (preferably, a tetrahydrofuryl group, a tetrahydropyranyl group, a pyrrolidinyl group, a piperidyl group, an azepanyl group, an azocanyl group, a morpholinyl group (including a morpholino group), a 1, 1-dioxideisothiazolidinyl group, an oxazolidinyl group, an imidazolidinyl group) optionally substituted with 1 to 3 substituents selected from (i) a hydroxy group, (ii) a d6 alkyl group (preferably a methyl group) optionally substituted with 1 to 3 substituents selected from a hydroxy group and a C1-6 alkoxy group (preferably a methoxy group), (iii) a Ci_6 alkoxy group (preferably a methoxy group) and (iv) an oxo group, (g) a C3_6-oxy cycloalkyl group (preferably, a cyclopentyloxy group), (h) an aryl? ß - ?? - ??? (preferably, a phenoxy group), (i) a 5 or 6 membered unsaturated heterocyclyloxy group (preferably a pyridyloxy group), (j) a saturated 5- or 6-membered heterocyclyloxy group (preferably, a tetrahydrofuryloxy group, a tetrahydropyranyloxy group) and (k) an amino group optionally mono- or disubstituted with substituents selected from (i) a Ci_6 alkyl group (preferably a methyl group) optionally substituted with 1 to 3 substituents selected from a hydroxy group, a carboxy group and a carboxy-alkoxy group (preferably a carboxymethoxy group), (ii) a Ci_6-carbonyl alkyl group (preferably, an acetyl group, a propanoyl group, a 2-methylpropanoyl group, a 2,2-dimethylpropanoyl group, a 3-methylbutanoyl group) optionally substituted with 1 to 3 substituents selected from a hydroxy group and a Ci_6 alkoxy group (preferably a methoxy group), (iii) a C 1 -carbonyl alkoxy group (preferably, a methoxycarbonyl group, a tert-butoxycarbonyl group) optionally substituted with aryl groups ββ- ?? (preferably, a phenyl group) and (iv) a cycloalkyl Ca-s-carbonyl group (preferably, a cyclopropylcarbonyl group, a cyclohexylcarbonyl group) optionally substituted with C 1-6 alkoxy groups (preferably, a methoxy group).
R8 is, more preferably, a Ci_6 alkyl group (preferably, a methyl group, an ethyl group, a propyl group, an isopropyl group) substituted with 1 to 3 substituents selected from (c) a C3_6 cycloalkyl group (preferably, a cyclopentyl group, a cyclohexyl group) optionally substituted with Ci_6 alkoxy groups (preferably a methoxy group), (d) a C6-10 aryl group (preferably, a phenyl group), (e) a 5 or 6 membered unsaturated heterocyclic group (preferably, an imidazolyl group, a dihydropyridyl group, a pyrazolyl group) optionally substituted with oxo groups and (f) a saturated 5- to 8-membered heterocyclic group (preferably, a morpholinyl group (including a morpholino group)) optionally substituted with 1 to 3 substituents selected from (i) a hydroxy group, (I) a Ci_6 alkyl group (preferably a methyl group) optionally substituted with 1 to 3 substituents selected from a hydroxy group and an Ci_s alkoxy group (preferably a methoxy group), (iii) a C-i_6 alkoxy group (preferably a methoxy group) and (iv) an oxo group.
R8 is, with particular preference, a C-i_s alkyl group (preferably a methyl group, an ethyl group) substituted with saturated 5- to 8-membered heterocyclic groups (preferably a morpholino group) optionally substituted with 1 to 3 substituents selected from (i) a hydroxy group, (ii) an Ci_s alkyl group (preferably a methyl group) optionally substituted with 1 to 3 substituents selected from a hydroxy group and a Ci_6 alkoxy group (preferably a methoxy group), (iii) a Ci_6 alkoxy group (preferably a methoxy group) and (iv) an oxo group.
Alternatively, R7 and R8 can form, together with the nitrogen atom and the carbon atom to which they are attached, a cyclic amine of 5 or 6 members substituted with an oxo group (preferably 2-oxopyrrolidine, 2-oxopiperidine , 2-oxooxazolidine) and also optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a Ci_6 alkyl group (preferably, a methyl group) optionally substituted with a hydroxy group, (c) a Ci_6 alkoxy group (preferably a methoxy group) and (d) a C3_6 cycloalkyl group (preferably, a cyclohexyl group).
As a compound [I], a compound where R1 is (1) a hydrogen atom, (2) a hydroxy group or (3) a C-i_6 alkoxy group (preferably, a methoxy group, an isopropoxy group) optionally substituted with C6-10 aryl groups (preferably, a phenyl group); R2 and R3 are the same or different and each one is (1) a hydrogen atom, or (2) a C-i_6 alkyl group (preferably, a methyl group) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group and (b) a C 1-6 alkoxy group (preferably, a methoxy group); and R4 is which is attached to position 5 or position 6 of the indole ring or which is attached to the 6-position of the indole ring (preferably, which is attached to position 6 of the indole ring), where R5 is (1) a hydrogen atom, or 2) a Ci_6 alkyl group (preferably, a methyl group, an ethyl group), and R6 is (1) a hydrogen atom, (2) a Cie alkyl group (preferably a methyl group, an ethyl group, an isopropyl group, an isobutyl group, a tert-butyl group, a neopentyl group, a 1,2-dimethylpropyl group, a 1, 2 group , 2-trimethylpropyl) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a C 1-4 alkoxy group (preferably, a methoxy group, a propoxy group, an isopropoxy group), (c) a carboxy group, (d) a Ci_6-carbonyl alkoxy group (preferably a methoxycarbonyl group, a tert-butoxycarbonyl group), (e) a C5-10 aryl group (preferably, a phenyl group), (f) an aryl? ß - ?? - ??? (preferably, a phenoxy group), (g) an amino group optionally mono- or disubstituted with C 1-4 alkyl groups (preferably a methyl group), (h) a 5 or 6 membered unsaturated heterocyclic group (preferably, a furyl group, a pyrrolyl group, a thiazolyl group, a tetrazolyl group, an imidazolyl group) optionally substituted with Ci_6 alkyl groups (preferably a methyl group) Y (i) a saturated 5- or 6-membered heterocyclic group (preferably a morpholinyl group), (3) a Ci_6 alkoxy group (preferably a methoxy group), (4) a C6-10 aryl group (preferably, a phenyl group), or (5) a 5 or 6 membered unsaturated heterocyclic group (preferably, a 1,3-thiadiazolyl group) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group and (b) an alkoxy group C-i_6 (preferably a methoxy group) or R5 and R6 form, together with the nitrogen atom to which they are attached, a cyclic amine of 5 or 6 members (preferably pyrrolidine, piperidine, piperazine, morpholine) (the cyclic amine is optionally condensed with an unsaturated heterocycle of 5 or 6 members (preferably imidazole)) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a C-i_6 alkyl group (preferably, a methyl group, an ethyl group), (c) a Ci_6 alkoxy group (preferably a methoxy group) and (d) a Ci -s-carbonyl alkoxy group (preferably, a tert-butoxycarbonyl group); R7 is (1) a hydrogen atom, or (2) a C-i_6 alkyl group (preferably, a methyl group, an ethyl group, a propyl group) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) an alkoxy group Ci_e (preferably a methoxy group) and (c) an amino group optionally mono- or disubstituted with Ci_6 alkyl groups (preferably a methyl group) [preferably, a Ci_6 alkyl group (preferably, a methyl group, an ethyl group, a propyl group) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a Ci_6 alkoxy group (preferably a methoxy group) and (c) an amino group optionally mono- or disubstituted with Ci_6 alkyl groups (preferably a methyl group)], and R8 is (1) a Ci_6 alkyl group (preferably, a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a tert-butyl group, a neopentyl group) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) an alkoxy group Ci_e (preferably, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group) optionally substituted with aryl groups Ce- ?? (preferably, a phenyl group), (c) a C3_6 cycloalkyl group (preferably, a cyclopentyl group, a cyclohexyl group) optionally substituted with d6 alkoxy groups (preferably a methoxy group), (d) an aryl group C & -10 (preferably, a phenyl group), (e) a 5 or 6 membered unsaturated heterocyclic group (preferably, an imidazolyl group, a dihydropyridyl group, a pyrazolyl group) optionally substituted with oxo groups, (f) a saturated 5- to 8-membered heterocyclic group (preferably, a tetrahydrofuryl group, a tetrahydropyranyl group, a pyrrolidinyl group, a piperidyl group, an azepanyl group, an azocanyl group, a morpholinyl group (including a morpholino group), a 1, 1-dioxideisothiazolidinyl group, an oxazolidinyl group, an imidazolidinyl group) optionally substituted with 1 to 3 substituents selected from (i) a hydroxy group, ii) a Ci_6 alkyl group (preferably a methyl group) optionally substituted with 1 to 3 substituents selected from a hydroxy group and a C 1-6 alkoxy group (preferably a methoxy group), (iii) a C 1-6 alkoxy group (preferably a methoxy group) and (iv) an oxo group, (g) a C3_6-oxy cycloalkyl group (preferably, a cyclopentyloxy group), (h) an aryl C6-io-oxy group (preferably a phenoxy group), (i) an unsaturated 5- or 6-membered heterocyclyloxy group (preferably a pyridyloxy group), G) a 5- or 6-membered saturated heterocyclyloxy group (preferably a tetrahydrofuryloxy group, a tetrahydropyranyloxy group) and (k) an amino group optionally mono- or disubstituted with substituents selected from (1) a C-i_6 alkyl group (preferably a methyl group) optionally substituted with 1 to 3 substituents selected from a hydroxy group, a carboxy group and a carboxy-C 1-6 alkoxy group (preferably a carboxymethoxy group), (ii) an alkyl C 1 -carbonyl group (preferably, an acetyl group, a propanoyl group, a 2-methylpropanoyl group, a 2,2-dimethylpropanoyl group, a 3-methylbutanoyl group) optionally substituted with 1 to 3 selected substituents of a hydroxy group and a C-i_6 alkoxy group (preferably a methoxy group), (iii) a Ci_6-carbonyl alkoxy group (preferably a methoxycarbonyl group, a tert-butoxycarbonyl group) optionally substituted with aryl groups? e- ?? (preferably, a phenyl group) and (iv) a C3_6-carbonyl cycloalkyl group (preferably, a cyclopropylcarbonyl group, a cyclohexylcarbonyl group) optionally substituted with C-i-s alkoxy groups (preferably a methoxy group), (2) a Ci_6 alkoxy group (preferably a methoxy group) optionally substituted with aryl Ce-io groups (preferably a phenyl group), (3) a C3-6 cycloalkyl group (preferably, a cyclopentyl group, a cyclohexyl group) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group and (b) an alkoxy group Ci_e (preferably a methoxy group), (4) a C6-10 aryl group (preferably a phenyl group) optionally substituted with a Ci_6 alkyl group (preferably a methyl group) optionally substituted with 1 to 3 halogen atoms (preferably a fluorine atom) , (5) an amino group optionally mono- or disubstituted with C1-6 alkyl groups (preferably a methyl group) optionally substituted with aryl groups Ce- ?? (preferably, a phenyl group), (6) a 5 or 6 membered unsaturated heterocyclic group (preferably, an isoxazolyl group) optionally substituted with d6 alkyl groups (preferably a methyl group), (7) a saturated 5- or 6-membered heterocyclic group (preferably, a tetrahydrofuryl group, a tetrahydropyranyl group, a pyrrolidinyl group, a piperidyl group) optionally substituted with 1 to 3 substituents selected from (a) a C-i_6 alkyl group (preferably a methyl group), (b) an alkyl d-e-carbonyl group (preferably an acetyl group) and (c) an oxo group, (8) a C3_s-oxy cycloalkyl group (preferably a cyclohexyloxy group), or (9) an aryl C6-io-carbonyl group (preferably, a group benzoyl) or R7 and R8 form, together with the nitrogen atom and the carbon atom to which they are attached, a cyclic amine of 5 or 6 members substituted with an oxo group (preferably 2-oxopyrrolidine, 2-oxopiperidine, 2-oxooxazolidine) and also optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a C-i_6 alkyl group (preferably a methyl group) optionally substituted with hydroxy groups, (c) a C-i-6 alkoxy group (preferably a methoxy group) and (d) a C3_6 cycloalkyl group (preferably, a cyclohexyl group).
In particular, a compound is preferred where R1 is (1) a hydrogen atom, (2) a hydroxy group, or (3) a Ci_6 alkoxy group (preferably, a methoxy group, an isopropoxy group) optionally substituted with C6-10 aryl groups (preferably, a phenyl group); R2 and R3 are the same or different and each one is (1) a hydrogen atom, or (2) a C 1-6 alkyl group (preferably, a methyl group) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group and (b) a Ci_6 alkoxy group (preferably, a methoxy group); R4 is which is attached to position 6 of the indole ring, where R7 is a Ci_6 alkyl group (preferably, a methyl group, an ethyl group, a propyl group) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a C 1-6 alkoxy group (preferably a methoxy group) and (c) an amino group optionally mono- or disubstituted with Ci_6 alkyl groups (preferably a methyl group), and R8 is (1) a Ci_6 alkyl group (preferably, a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a tert-butyl group, a neopentyl group) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a C-i_6 alkoxy group (preferably a methoxy group, a ethoxy group, a propoxy group, an isopropoxy group) optionally substituted with C6-10 aryl groups (preferably, a phenyl group), (c) a C3-6 cycloalkyl group (preferably, a cyclopentyl group, a cyclohexyl group) optionally substituted with Ci_s alkoxy groups (preferably a methoxy group), (d) an aryl group C ^ o (preferably a phenyl group), (e) a 5 or 6 membered unsaturated heterocyclic group (preferably, an imidazolyl group, a dihydropyridyl group, a pyrazolyl group) optionally substituted with oxo groups, (f) a saturated 5- to 8-membered heterocyclic group (preferably, a tetrahydrofuryl group, a tetrahydropyranyl group, a pyrrolidinyl group, a piperidyl group, an azepanyl group, an azocanyl group, a morpholinyl group (including a morpholino group), a 1, 1-dioxideisothiazolidinyl group, an oxazolidinyl group, an imidazolidinyl group) optionally substituted with 1 to 3 substituents selected from (i) a hydroxy group, (ii) a C 1-6 alkyl group (preferably, a methyl group) optionally substituted with 1 to 3 substituents selected from a hydroxy group and a C 1-6 alkoxy group (preferably a methoxy group), (iii) a Ci_6 alkoxy group (preferably a methoxy group) and (iv) an oxo group, (g) a C3-6-0XI cycloalkyl group (preferably a cyclopentyloxy group), (h) an aryl C6-io-oxy group (preferably a phenoxy group), (i) a 5 or 6 membered unsaturated heterocyclyloxy group (preferably a pyridyloxy group), (j) a saturated 5- or 6-membered heterocyclyloxy group (preferably, a tetrahydrofuryloxy group, a tetrahydropyranyloxy group) and (k) an amino group optionally mono- or disubstituted with substituents selected from (1) a Ci_6 alkyl group (preferably a methyl group) optionally substituted with 1 to 3 substituents selected from a hydroxy group, a carboxy group and a carboxy-alkoxy group (preferably a carboxymethoxy group), (ii) a Ci_6-carbonyl alkyl group (preferably, an acetyl group, a propanoyl group, a 2-methylpropanoyl group, a 2,2-dimethylpropanoyl group, a 3-methylbutanoyl group) optionally substituted with 1 to 3 substituents selected from a hydroxy group and an alkoxy group (preferably a methoxy group), (iii) a Ci_6-carbonyl alkoxy group (preferably, a methoxycarbonyl group, a tert-butoxycarbonyl group) optionally substituted with aryl groups ß-? (preferably, a phenyl group) and (iv) a C3-6 carbonyl cycloalkyl group (preferably a cyclopropylcarbonyl group, a cyclohexylcarbonyl group) optionally substituted with Ci_6 alkoxy groups (preferably a methoxy group), (2) a Ci_6 alkoxy group (preferably a methoxy group) optionally substituted with C5_i0 aryl groups (preferably, a phenyl group), (3) a C3_6 cycloalkyl group (preferably, a cyclopentyl group, a cyclohexyl group) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group and (b) a Ci_6 alkoxy group (preferably a methoxy group), (4) a C6-10 aryl group (preferably a phenyl group) optionally substituted with an alkyl group (preferably a methyl group) optionally substituted with 1 to 3 halogen atoms (preferably a fluorine atom), (5) an amino group optionally mono- or disubstituted with alkyl groups d_6 (preferably, a methyl group) optionally substituted with aryl groups Ce- ?? (preferably, a phenyl group), (6) a 5 or 6 membered unsaturated heterocyclic group (preferably, an isoxazolyl group) optionally substituted with alkyl groups Ci_6 (preferably a methyl group), (7) a saturated 5- or 6-membered heterocyclic group (preferably, a tetrahydrofuryl group, a tetrahydropyranyl group, a pyrrolidinyl group, a piperidyl group) optionally substituted with 1 to 3 substituents selected from (a) a C-i_6 alkyl group (preferably a methyl group), (b) an alkyl C 1 -carbonyl group (preferably, a group acetyl) and (c) an oxo group, (8) a cycloalkyl group C ^ -oxi (preferably a cyclohexyloxy group), or (9) an aryl C6-io-carbonyl group (preferably a benzoyl group) or R7 and R8 form, together with the nitrogen atom and the carbon atom to which they are attached, a cyclic amine of 5 or 6 members substituted with an oxo group (preferably 2-oxopyrrolidine, 2-oxopiperidine, 2-oxooxazolidine) and also optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a Ci_6 alkyl group (preferably a methyl group) optionally substituted with hydroxy groups, (c) a Ci_6 alkoxy group (preferably a methoxy group) and (d) a C3_6 cycloalkyl group (preferably a cyclohexyl group), that is, a compound represented by the aforementioned formula [1-a] is particularly preferred.
As a compound represented by the formula [I-a], a compound wherein R1 is a hydrogen atom; R2 and R3 are the same or different and each is a Ci_e alkyl group (preferably a methyl group); R7 is a Ci_6 alkyl group (preferably, a methyl group, an ethyl group, a propyl group), and R8 is a Ci_e alkyl group (preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a tert-butyl group, a neopentyl group) substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a C 1-6 alkoxy group (preferably, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group) optionally substituted with aryl groups? (preferably, a phenyl group), (c) a C3-3 cycloalkyl group (preferably a cyclopentyl group, a cyclohexyl group) optionally substituted with C1_6 alkoxy groups (preferably a methoxy group), (d) a C6-10 aryl group (preferably, a phenyl group), (e) a 5 or 6 membered unsaturated heterocyclic group (preferably, an imidazolyl group, a dihydropyridyl group, a pyrazolyl group) optionally substituted with oxo groups, (f) a saturated 5- to 8-membered heterocyclic group (preferably, a tetrahydrofuryl group, a tetrahydropyranyl group, a pyrrolidinyl group, a piperidyl group, an azepanyl group, an azocanyl group, a morpholinyl group (including a morpholino group), a 1, 1-dioxideisothiazolidinyl group, an oxazolidinyl group, an imidazolidinyl group) optionally substituted with 1 to 3 substituents selected from (i) a hydroxy group, (ii) a Ci_6 alkyl group (preferably a methyl group) optionally substituted with 1 to 3 substituents selected from a hydroxy group and an alkoxy group Ci_e (preferably a methoxy group), (iii) a Ci_6 alkoxy group (preferably a methoxy group) and (iv) an oxo group, (g) a cycloalkyl group C ^ -e-oxy (preferably a cyclopentyloxy group), (h) an aryl C6-io-o group (preferably a phenoxy group), (i) a 5 or 6 membered unsaturated heterocyclyloxy group (preferably a pyridyloxy group), (j) a saturated 5- or 6-membered heterocyclyloxy group (preferably, a tetrahydrofuryloxy group, a tetrahydropyranyloxy group) and (k) an amino group optionally mono- or disubstituted with substituents selected from (i) an Ci_e alkyl group (preferably a methyl group) optionally substituted with 1 to 3 substituents selected from a hydroxy group, a carboxy group and a C 1 -6 carboxy-alkoxy group (preferably a carboxymethoxy group), (ii) an alkyl Ci -s-carbonyl group (preferably, an acetyl group, a propanoyl group, a 2-methylpropanoyl group, a 2,2-dimethylpropanoyl group, a 3-methylbutanoyl group) optionally substituted with 1 to 3 substituents selected from a hydroxy group and a C-i_6 alkoxy group (preferably a methoxy group), (iii) a Ci_6-carbonyl alkoxy group (preferably a methoxycarbonyl group, a tert-butoxycarbonyl group) optionally substituted with aryl groups Ce- ?? (preferably, a phenyl group) and (iv) a C3_6-carbonyl cycloalkyl group (preferably, a cyclopropylcarbonyl group, a cyclohexylcarbonyl group) optionally substituted with Ci-e alkoxy groups (preferably, a methoxy group).
In another embodiment, as compound [I], a compound represented by the above-mentioned formula [] is preferred (hereinafter, sometimes abbreviated as compound []). Each group of the compound [] is explained below.
R1 is (1) a hydrogen atom, (2) a hydroxy group, or (3) a Ci_6 alkoxy group (preferably, a methoxy group, an isopropoxy group) optionally substituted with C6-10 aryl groups (preferably, a phenyl group).
R2 and R3 are the same or different and each one is (1) a hydrogen atom, or (2) a C-i_s alkyl group (preferably, a methyl group) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group and (b) an alkoxy group Ci_e (preferably, a methoxy group).
R is a group represented by which is attached to position 5 or position 6 of the indole ring.
R is preferably which is attached to position 5 or position 6 of the indole ring or which is attached to position 6 of the indole ring, more preferably, which is attached to position 6 of the indole ring.
R5 'is (1) a hydrogen atom, or (2) a Ci_6 alkyl group (preferably, a methyl group, an ethyl group).
R6 'is (1) a hydrogen atom, (2) a C-i_6 alkyl group (preferably, a methyl group, an ethyl group, an isopropyl group, an isobutyl group, a tert-butyl group, a neopentyl group, a 1,2-dimethylpropyl group, a group 1 , 2,2-trimethylpropyl) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a Ci_6 alkoxy group (preferably a methoxy group, a propoxy group, an isopropoxy group), (c) a carboxy group, (d) a Ci_6-carbonyl alkoxy group (preferably a methoxycarbonyl group, a tert-butoxycarbonyl group), (e) an aryl group? ß- ?? (preferably, a phenyl group), (f) an aryl C6-io-oxy group (preferably a phenoxy group), (g) an amino group optionally mono- or disubstituted with Ci_6 alkyl groups (preferably a methyl group), (h) a 5 or 6 membered unsaturated heterocyclic group (preferably, a furyl group, a pyrrolyl group, a thiazolyl group, a tetrazolyl group, an imidazolyl group) optionally substituted with d6 alkyl groups (preferably a methyl group) Y (i) a saturated 5- or 6-membered heterocyclic group (preferably a morpholinyl group), (3) an alkoxy group Ci_6 (preferably a methoxy group), (4) an aryl group Ce-io (preferably a phenyl group), or (5) a 5 or 6 membered unsaturated heterocyclic group (preferably, a 1,3-thiadiazolyl group) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group and (b) a Ci_6 alkoxy group (preferably, a methoxy group).
Alternatively, R5 and R6 can form, together with the nitrogen atom to which they are attached, a cyclic amine of 5 or 6 members (preferably, pyrrolidine, piperidine, piperazine, morpholine) (the cyclic amine is optionally condensed with heterocycle 5 or 6 membered unsaturated (preferably imidazole)), which is optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a C-i_e alkyl group (preferably, a methyl group, a ethyl group), (c) a Ci_6 alkoxy group (preferably a methoxy group) and (d) a Ci_6-carbonyl alkoxy group (preferably, a tert-butoxycarbonyl group).
R7 'is (1) a hydrogen atom, or (2) a C-i_6 alkyl group (preferably, a methyl group, an ethyl group, a propyl group) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) an alkoxy group (preferably a methoxy group) and (c) an amino group optionally mono- or disubstituted with C-i_6 alkyl groups (preferably a methyl group), preferably a C-i_6 alkyl group (preferably, a methyl group, an ethyl group, a propyl group) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a Ci_6 alkoxy group (preferably a methoxy group) and (c) an amino group optionally mono- or disubstituted with C-i_6 alkyl groups (preferably, a methyl group).
R8 'is (1) an alkyl group (preferably, a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a tert-butyl group, a neopentyl group) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) an alkoxy group Ci_e (preferably, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group) optionally substituted with aryl groups Ce- ?? (preferably, a phenyl group), (c) a C3-6 cycloalkyl group (preferably, a cyclopentyl group, a cyclohexyl group) optionally substituted with Ci_6 alkoxy groups (preferably a methoxy group), (d) an aryl group Ce- ?? (preferably, a phenyl group), (e) a 5 or 6 membered unsaturated heterocyclic group (preferably, an imidazolyl group, a dihydropyridyl group, a pyrazolyl group) optionally substituted with oxo groups, (f) a saturated 5- to 8-membered heterocyclic group (preferably, a tetrahydrofuran group, a tetrahydropyranyl group, a pyrrolidinyl group, a piperidyl group, an azepanyl group, an azocanyl group, a morpholinyl group, a group 1, 1- dioxideisothiazolidinyl, an oxazolidinyl group, an imidazolidinyl group) optionally substituted with 1 to 3 substituents selected from (i) a hydroxy group, (ii) a Ci_6 alkyl group (preferably a methyl group) optionally substituted with 1 to 3 substituents selected from a hydroxy group and an alkoxy group Ci_e (preferably a methoxy group), (iii) a Ci_6 alkoxy group (preferably a methoxy group) and (iv) an oxo group, (g) a C3_6-oxy cycloalkyl group (preferably, a cyclopentyloxy group), (h) an aryl C6-io-oxy group (preferably a phenoxy group), (i) a 5 or 6 membered unsaturated heterocyclyloxy group (preferably a pyridyloxy group), (j) a saturated 5- or 6-membered heterocyclyloxy group (preferably, a tetrahydrofuryloxy group, a tetrahydropyranyloxy group) and (k) an amino group optionally mono- or disubstituted with substituents selected from (i) a Ci_6 alkyl group (preferably a methyl group), (ii) an alkyl Ci-carbonyl group (preferably, an acetyl group, a propanoyl group, a 2-methylpropanoyl group, a 2,2-dimethylpropanoyl group, a 3-methylbutanoyl group) optionally substituted with 1 to 3 selected substituents of a hydroxy group and a Ci_6 alkoxy group (preferably a methoxy group), (iii) a Ci_6-carbonyl alkoxy group (preferably, a methoxycarbonyl group, a tert-butoxycarbonyl group) optionally substituted with aryl groups ß-? (preferably, a phenyl group) and (iv) a C3_6-carbonyl cycloalkyl group (preferably, a cyclopropylcarbonyl group, a cyclohexylcarbonyl group) optionally substituted with Ci_6 alkoxy groups (preferably a methoxy group), (2) an alkoxy group (preferably a methoxy group) optionally substituted with C 1 io ary groups (preferably a phenyl group), (3) a C3-6 cycloalkyl group (preferably, a cyclopentyl group, a cyclohexyl group) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group and (b) an alkoxy group Ci_e (preferably a methoxy group), (4) an aryl group Ce- ?? (preferably, a phenyl group) optionally substituted with Ci_e alkyl groups (preferably a methyl group) optionally substituted with 1 to 3 halogen atoms (preferably a fluorine atom), (5) an amino group optionally mono- or disubstituted with Ci_e alkyl groups (preferably a methyl group) optionally substituted with C6-10 aryl groups (preferably a phenyl group), (6) a 5 or 6 membered unsaturated heterocyclic group (preferably, an isoxazolyl group) optionally substituted with Ci_6 alkyl groups (preferably a methyl group), (7) a saturated 5- or 6-membered heterocyclic group (preferably, a tetrahydrofuryl group, a tetrahydropyranyl group, a pyrrolidinyl group, a piperidyl group) optionally substituted with 1 to 3 substituents selected from (a) a Ci_6 alkyl group (preferably a methyl group), (b) an alkyl C-i6-carbonyl group (preferably an acetyl group) and (c) an oxo group, (8) a cycloalkyl group C ^ -o i (preferably a cyclohexyloxy group), or (9) an aryl C6-io-carbonyl group (preferably, a benzoyl group).
Alternatively, R7 and R8 can form, together with the nitrogen atom and the carbon atom to which they are attached, a cyclic amine of 5 or 6 members substituted with an oxo group (preferably 2-oxopyrrolidine, 2-oxopiperidine , 2-oxooxazolidine) and also optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a C 1-6 alkyl group (preferably, a methyl group) optionally substituted with hydroxy groups, (c) a C 1-6 alkoxy group (preferably a methoxy group) and (d) a C3-6 cycloalkyl group (preferably, a cyclohexyl group).
As compound [G], a compound is preferred where R1 'is (1) a hydrogen atom, (2) a hydroxy group, or (3) an alkoxy group Ci_6 (preferably a methoxy group, an isopropoxy group) optionally substituted with aryl groups Ce- ?? (preferably, a phenyl group); R2 and R3 are the same or different and each one is (1) a hydrogen atom, or (2) a C 1-6 alkyl group (preferably, a methyl group) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group and (b) a Ci_6 alkoxy group (preferably, a methoxy group); R is e attaches to position 5 or position 6 of the indole ring or is attached to position 6 of the indole ring (preferably which is attached to position 6 of the indole ring), where R5 'is (1) a hydrogen atom, or (2) a Ci_6 alkyl group (preferably, a methyl group, an ethyl group), and R6 'is (1) a hydrogen atom, (2) a C 1-6 alkyl group (preferably, a methyl group, an ethyl group, an isopropyl group, an isobutyl group, a tert-butyl group, a neopentyl group, a 1,2-dimethylpropyl group, a 1,2-group , 2-trimethylpropyl) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) an alkoxy group Ci_e (preferably, a methoxy group, a propoxy group, an isopropoxy group), (c) a carboxy group, (d) a d6-carbonyl alkoxy group (preferably a methoxycarbonyl group, a tert-butoxycarbonyl group), (e) a C6-10 aryl group (preferably, a phenyl group), (f) an aryl C6-io-oxy group (preferably a phenoxy group), (g) an amino group optionally mono- or disubstituted with Ci_6 alkyl groups (preferably a methyl group), (h) a 5 or 6 membered unsaturated heterocyclic group (preferably, a furyl group, a pyrrolyl group, a thiazolyl group, a tetrazolyl group, an imidazolyl group) optionally substituted with C-i_6 alkyl groups (preferably, a group methyl) and (i) a saturated 5- or 6-membered heterocyclic group (preferably a morpholinyl group), (3) a Ci_6 alkoxy group (preferably a methoxy group), (4) a C6-10 aryl group (preferably, a phenyl group), or (5) a 5 or 6 membered unsaturated heterocyclic group (preferably, a 1,3-thiadiazolyl group) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group and (b) a C1_s alkoxy group (preferably a methoxy group) or R5 and R6 form, together with the nitrogen atom to which they are attached, a cyclic amine of 5 or 6 members (preferably pyrrolidine, piperidine, piperazine, morpholine) (the cyclic amine is optionally condensed with an unsaturated heterocycle of 5 or 6 members (preferably imidazole)), which is optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a Ci_6 alkyl group (preferably, a methyl group, an ethyl group), (c) a Ci_6 alkoxy group (preferably a methoxy group) and (d) a Ci_6-carbonyl alkoxy group (preferably, a tert-butoxycarbonyl group); R7"is (1) a hydrogen atom, or (2) a Ci_6 alkyl group (preferably, a methyl group, an ethyl group, a propyl group) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a Ci_6 alkoxy group (preferably a methoxy group) and (c) an amino group optionally mono- or disubstituted with Ci_6 alkyl groups (preferably a methyl group) [preferably, a Ci_6 alkyl group (preferably, a methyl group, an ethyl group, a propyl group) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a Ci_6 alkoxy group (preferably a methoxy group) and (c) an amino group optionally mono- or disubstituted with Ci_s alkyl groups (preferably a methyl group)], and R8 'is (1) a Ci_6 alkyl group (preferably, a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a tert-butyl group, a neopentyl group) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a Ci_6 alkoxy group (preferably, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group) optionally substituted with aryl Ce-io groups (preferably, a phenyl group), (c) a C 3-6 cycloalkyl group (preferably, a cyclopentyl group, a cyclohexyl group) optionally substituted with Ci_6 alkoxy groups (preferably a methoxy group), (d) a C6-10 aryl group (preferably, a phenyl group), (e) a 5 or 6 membered unsaturated heterocyclic group (preferably, an imidazolyl group, a dihydropyridyl group, a pyrazolyl group) optionally substituted with oxo groups, (f) a saturated 5- to 8-membered heterocyclic group (preferably, a tetrahydrofuryl group, a tetrahydropyranyl group, a pyrrolidinyl group, a piperidyl group, an azepanyl group, an azocanyl group, a morpholinyl group, a 1, 1- group dioxideisothiazolidinyl, an oxazolidinyl group, an imidazolidinyl group) optionally substituted with 1 to 3 substituents selected from (i) a hydroxy group, (I) a Ci_6 alkyl group (preferably a methyl group) optionally substituted with 1 to 3 substituents selected from a hydroxy group and an alkoxy group (preferably a methoxy group), (iii) a Ci_6 alkoxy group (preferably a methoxy group) and (iv) an oxo group, (g) a cycloalkyl group C ^ -oxi (preferably a cyclopentyloxy group), (h) an aryl C6_io-oxy group (preferably a phenoxy group), (i) a 5- or 6-membered unsaturated heterocyclyloxy group (preferably a pyridyloxy group), (j) a saturated 5- or 6-membered heterocyclyloxy group (preferably, a tetrahydrofyloxy tetrahydroxy group, a tetrahydropyranyloxy group) and (k) an amino group optionally mono- or disubstituted with substituents selected from (1) a Ci_6 alkyl group (preferably a methyl group), (ii) a C 1 -s-carbonyl alkyl group (preferably, an acetyl group, a propanoyl group, a 2-methylpropanoyl group, a 2,2-dimethylpropanoyl group, a 3-methylbutanoyl group) optionally substituted with 1 to 3 substituents selected from a hydroxy group and a Ci_6 alkoxy group (preferably a methoxy group), (iii) a Ci -s-carbonyl alkoxy group (preferably, a methoxycarbonyl group, a tert-butoxycarbonyl group) optionally substituted with aryl groups Ce- ?? (preferably, a phenyl group) and (iv) a C3_6-carbonyl cycloalkyl group (preferably a cyclopropylcarbonyl group, a cyclohexylcarbonyl group) optionally substituted with C1_6 alkoxy groups (preferably a methoxy group), (2) a Ci_6 alkoxy group (preferably, a methoxy group) optionally substituted with aryl? Β- ?? (preferably, a phenyl group), (3) a C3-5 cycloalkyl group (preferably, a cyclopentyl group, a cyclohexyl group) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group and (b) a Ci_6 alkoxy group (preferably a methoxy group), (4) a C6-10 aryl group (preferably a phenyl group) optionally substituted with Ci_6 alkyl groups (preferably a methyl group) optionally substituted with 1 to 3 halogen atoms (preferably a fluorine atom), (5) an amino group optionally mono- or disubstituted with Ci_s alkyl groups (preferably a methyl group) optionally substituted with C6-10 aryl groups (preferably a phenyl group), (6) a 5 or 6 membered unsaturated heterocyclic group (preferably, an isoxazolyl group) optionally substituted with alkyl groups (preferably, a methyl group), (7) a saturated 5- or 6-membered heterocyclic group (preferably, a tetrahydrofuryl group, a tetrahydropyranyl group, a pyrrolidinyl group, a piperidyl group) optionally substituted with 1 to 3 substituents selected from (a) a C1-6 alkyl group (preferably a methyl group), (b) an alkyl C-i6-carbonyl group (preferably an acetyl group) and (c) an oxo group, (8) a C3_6-oxy cycloalkyl group (preferably, a cyclohexyloxy group), or (9) an aryl C6-io-carbonyl group (preferably a benzoyl group) or R7 and R8 form, together with the nitrogen atom and the carbon atom to which they are attached, a cyclic amine of 5 or 6 members substituted with an oxo group (preferably 2-oxopyrrolidine, 2-oxopiperidine, 2-oxooxazolidine) and also optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a C-i_6 alkyl group (preferably a methyl group) optionally substituted with hydroxy groups, (c) a C-i-e alkoxy group (preferably a methoxy group) and (d) a C3-6 cycloalkyl group (preferably, a cyclohexyl group).
Among the above, a compound is particularly preferred where Rr is (1) a hydrogen atom, (2) a hydroxy group, or (3) a Ci_6 alkoxy group (preferably, a methoxy group, an isopropoxy group) optionally substituted with C6-10 aryl groups (preferably, a phenyl group); R2 and R3 are the same or different and each one is (1) a hydrogen atom, or (2) a C-i_6 alkyl group (preferably, a methyl group) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group and (b) an alkoxy group Ci-s (preferably, a methoxy group); R is which is attached to position 6 of the indole ring, where R7 is a C-i_6 alkyl group (preferably, a methyl group, an ethyl group, a propyl group) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) an alkoxy group Ci_s (preferably, a methoxy group) and (c) an amino group optionally mono- or disubstituted with alkyl groups (preferably a methyl group), and R8 is (1) a Ci_s alkyl group (preferably, a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a tert-butyl group, a neopentyl group) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a Ci_6 alkoxy group (preferably, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group) optionally substituted with C6-10 aryl groups (preferably, a phenyl group), (c) a C3_6 cycloalkyl group (preferably a cyclopentyl group, a cyclohexyl group) optionally substituted with Ci_6 alkoxy groups (preferably a methoxy group), (d) an aryl group Ce- ?? (preferably, a phenyl group), (e) a 5 or 6 membered unsaturated heterocyclic group (preferably, an imidazolyl group, a dihydropyridyl group, a pyrazolyl group) optionally substituted with oxo groups, (f) a saturated 5- to 8-membered heterocyclic group (preferably, a tetrahydrofuran group, a tetrahydropyranyl group, a pyrrolidinyl group, a piperidyl group, an azepanyl group, an azocanyl group, a morpholinyl group, a group , 1- dioxideisothiazolidinyl, an oxazolidinyl group, an imidazolidinyl group) optionally substituted with 1 to 3 substituents selected from (i) a hydroxy group, (ii) an alkyl group Ci_e (preferably a methyl group) optionally substituted with 1 to 3 substituents selected from a hydroxy group and a Ci- "alkoxy group (preferably a methoxy group), (iii) a C 1-6 alkoxy group (preferably a methoxy group) and (iv) an oxo group, (g) a C3_6-oxy cycloalkyl group (preferably, a cyclopentyloxy group), (h) an aryl? ß - ?? - ??? (preferably, a phenoxy group), (i) a 5 or 6 membered unsaturated heterocyclyloxy group (preferably a pyridyloxy group), (j) a saturated 5- or 6-membered heterocyclyloxy group (preferably, a tetrahydrofuryloxy group, a tetrahydropyranyloxy group) and (k) an amino group optionally mono- or disubstituted with substituents selected from (i) an alkyl group (preferably a methyl group), (ii) a Ci_6-carbonyl alkyl group (preferably, an acetyl group, a propanoyl group, a 2-methylpropanoyl group, a 2,2-dimethylpropanoyl group, a 3-methylbutanoyl group) optionally substituted with 1 to 3 substituents selected from a hydroxy group and a C-i_6 alkoxy group (preferably a methoxy group), iii) a C 1 -6-carbonyl alkoxy group (preferably a methoxycarbonyl group, a tert-butoxycarbonyl group) optionally substituted with aryl Ce-1 groups (preferably a phenyl group) and (iv) a C3_ € -carbonyl cycloalkyl group (preferably a cyclopropylcarbonyl group, a cyclohexylcarbonyl group) optionally substituted with C1_6 alkoxy groups (preferably a methoxy group), (2) a Ci_6 alkoxy group (preferably a methoxy group) optionally substituted with aryl groups Ce- ?? (preferably, a phenyl group), (3) a C3_6 cycloalkyl group (preferably, a cyclopentyl group, a cyclohexyl group) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group and (b) an alkoxy group C-i_6 (preferably a methoxy group), (4) an aryl group Ce- ?? (preferably, a phenyl group) optionally substituted with Ci_6 alkyl groups (preferably a methyl group) optionally substituted with 1 to 3 halogen atoms (preferably, a fluorine atom), (5) an amino group optionally mono- or disubstituted with Ci_6 alkyl groups (preferably a methyl group) optionally substituted with C6-10 aryl groups (preferably a phenyl group), (6) a 5 or 6 membered unsaturated heterocyclic group (preferably, an isoxazolyl group) optionally substituted with alkyl groups Ci_s (preferably a methyl group), (7) a 5 or 6 membered saturated heterocyclic group (preferably, a tetrahydrofuran group, a tetrahydropyranyl group, a pyrrolidinyl group, a piperidyl group) optionally substituted with 1 to 3 substituents selected from (a) an Ci_s alkyl group (preferably a methyl group), (b) a Ci_6-carbonyl alkyl group (preferably an acetyl group) and (c) an oxo group, (8) a C3-6-oxy cycloalkyl group (preferably, a cyclohexyloxy group), or (9) an aryl C6-io-carbonyl group (preferably a benzoyl group) or R7 and R8 form, together with the nitrogen atom and the carbon atom to which they are attached, a cyclic amine of 5 or 6 members substituted with an oxo group (preferably 2-oxopyrrolidine, 2-oxopiperidine, 2-oxooxazolidine) and also optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) an alkyl group (preferably, a methyl group) optionally substituted with hydroxy groups, (c) a Ci_6 alkoxy group (preferably a methoxy group) and (d) a cycloalkyl group (preferably a cyclohexyl group), that is, a compound represented by the aforementioned formula [l'-a].
A pharmaceutically acceptable salt of compound [I] can be any salt as long as it forms a non-toxic salt of the compound of the present invention, and its examples include salts with inorganic acid, salts with organic acid, salts with inorganic base, salts with organic base , salts with amino acid, and the like.
Examples of the salts with inorganic acid include salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrobromic acid, and the like.
Examples of salts with organic acid include salts with oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like.
Examples of the salts with inorganic base include sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt, and the like.
Examples of the salts with organic base include salts with methylamine, diethylamine, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tris (hydroxymethyl) methylamine, dicyclohexylamine, β, β'-dibenzylethylenediamine, guanidine, pyridine, picoline, choline, cinchonin, meglumine, and the like.
Examples of the salts with amino acid include salts with lysine, arginine, aspartic acid, glutamic acid, and the like.
When a salt of the compound [I] is desired, each salt can be obtained by the reaction of the compound [I] with the inorganic base, organic base, inorganic acid, organic acid or amino acid according to a known method.
The "solvate" is a compound [I] or a pharmaceutically salt acceptable from this, which coordinates with a solvent molecule, and also covers hydrates. The solvate is preferably a pharmaceutically acceptable solvate, examples of this include a hydrate, ethanolate, dimethylsulfoxide, and the like of the compound [I] or a pharmaceutically acceptable salt thereof. Specific examples include semihydrate, 1 hydrate, 2 hydrate or 1 ethanolate of compound [I], 1 hydrate of the sodium salt or 2/3 ethanolate of 2-hydrochloride of compound [I], and the like.
The solvates can be obtained by a known method.
In addition, several "isomers" are present in a compound represented by the formula [I]. For example, the cis form and the trans form are present as geometric isomers, and when an asymmetric carbon is present, the enantiomers and diastereomers are present as stereoisomers due to the asymmetric carbon atom. In addition, when the axis of symmetry is present, the stereoisomers are present due to the axis of symmetry. Tautomers may also be present in some cases.
Alternatively, stereoisomers derived from the direction of a pair of non-shared electrons on the nitrogen atom may also be present. Accordingly, all these isomers and their mixtures are encompassed within the scope of the present invention.
In addition, the compound [I] can be labeled with isotopes (e.g., 3H, 1 C, 35S, etc.).
A deuterium converter obtained by the H conversion of the compound [I] to 2H (D) is also encompassed in a compound represented by the formula [I].
As the compound [I] or a pharmaceutically acceptable salt thereof or a solvate thereof, a compound [I] or a pharmaceutically acceptable salt thereof or a solvate thereof is substantially purified. More preferably it is the compound [I] or a pharmaceutically acceptable salt thereof or a solvate thereof, which is purified to have a purity of more than 80%.
In the present invention, a prodrug of the compound [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof (hereinafter sometimes abbreviated as the compound of the present invention) may also be a useful medicament. The "prodrug" is a derivative of the compound of the present invention having a degradable group in chemical or metabolic form which, after administration to the body, restores the original compound, for example, by hydrolysis, solvolysis or decomposition under physiological conditions, and shows intrinsic efficacy. It includes a non-covalent complex and a salt. The prodrug is used for, for example, increasing the absorption of oral administration, or targeting a white residue.
Examples of the modified moiety include, in the compound of the present invention, a highly functional reactive group such as a hydroxyl group, a carboxyl group, an amino group, and the like.
Specific examples of the hydroxyl modifying group include an acetyl group, a propanonyl group, a 2-methylpropanoyl group, a 2,2-dimethylpropanoyl group, a palmitoyl group, a benzoyl group, a 4-methylbenzoyl group, a dimethylcarbamoyl group, a dimethylaminomethylcarbonyl group, a sulfo group, an alanyl group, a fumaryl group, a 3-carboxybenzoyl group, a 2-carboxyethylcarbonyl group, a 3-sodium carboxy-benzoyl group, and the like.
Specific examples of the carboxyl modifying group include a methyl group, an ethyl group, a propanoyl group, a 2-methylpropanoyl group, a butyl group, an isobutyl group, a tert-butyl group, a 2,2-dimethylpropanoyloxymethyl group, a carboxymethyl group, a dimethylaminomethyl group, a 1- (acetyloxy) ethyl group, a 1- (ethoxycarbonyloxy) ethyl group, a 1- (isopropyloxycarbonyloxy) ethyl group, a 1- (cyclohexyloxycarbonyloxy) ethyl group, a group (5-methyl- 2-oxo-1,3-dioxol-4-yl) methyl, a benzyl group, a phenyl group, an o-tolyl group, a morpholinoethyl group, a?,? -diethylcarbamoylmethyl group, a phthalidyl group, and the like.
Specific examples of the amino modifying group include a tert-butyl group, a docosanoyl group, a 2,2-dimethylpropanoylmethyloxy group, an alanyl group, a hexylcarbamoyl group, a pentylcarbamoyl group, a 3-methylthio-1- (acetylamino) group propylcarbonyl, a 1-sulfo-1- (3-ethoxy-4-hydroxyphenyl) methyl group, a group (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl, a group (5-methyl) -2-oxo-1, 3-dioxol-4-yl) methoxycarbonyl, a tetrahydrofuranyl group, a pyrrolidylmethyl group, and the like.
When the indole compound of the present invention is used as a medicament, in particular a pharmaceutical composition, a chemically stable compound is preferred.
Examples of the "pharmaceutical composition" include oral preparations such as tablet, capsule, granule, powder, lozenge, syrup, emulsion, suspension and the like, and parenteral agents such as external preparation, suppository, injection, eye drops, nasal preparations, pulmonary and the like.
The pharmaceutical composition of the present invention is produced according to a method known in the art of pharmaceutical preparations, by mixing, etc. of the compound of the present invention with a suitable amount of at least one class of pharmaceutically acceptable carrier and the like as appropriate. While the content of the compound of the present invention in the pharmaceutical composition varies according to the dosage form, dosage and the like, it is, for example, 0.1 to 100% by weight of the total composition.
Examples of the "pharmaceutically acceptable carrier" include various organic and inorganic carrier substances conventionally used as preparation materials, for example, excipient, disintegrant, binder, glidant, lubricant and the like for solid preparations, and solvent, solubilizing agent, suspending agent , isotonicity agent, buffering agent, softening agent and the like for liquid preparations. When necessary, additives such as preservative, antioxidant, colorant, sweetening agent and the like are also used.
Examples of the "excipient" include lactose, sucrose, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, calcium carmellose, sodium carboxymethylstarch, low substituted hydroxypropylcellulose, gum arabic, and the like.
Examples of the "disintegrant" include carmellose, carmellose calcica, carmellose sodium, carboxymethylstarch sodium, croscarmellose sodium, crospovidone, low substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline cellulose, and the like.
Examples of the "binder" include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, gum arabic, and the like.
Examples of the "glidant" include light anhydrous silicic acid, magnesium stearate, and the like.
Examples of the "lubricant" include magnesium stearate, calcium stearate, talc, and the like.
Examples of the "solvent" include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, olive oil, and the like.
Examples of "solubilizing agents" include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate, and the like.
Examples of the "suspending agent" include benzalkonium chloride, carmellose, hydroxypropylcellulose, propylene glycol, povidone, methylcellulose, glycerol monostearate, and the like.
Examples of the "isotonicity agent" include glucose, D-sorbitol, sodium chloride, D-mannitol and the like.
Examples of the "buffering agent" include sodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate, and the like.
Examples of the "softening agent" include benzyl alcohol, and the like.
Examples of the "preservative" include ethyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid, and the like.
Examples of the "antioxidant" include sodium sulfite, ascorbic acid, and the like.
Examples of the "dye" include food dyes (e.g., Red Color No. 2 or 3, or Yellow Color No. 4 or 5 etc.), β-carotene, and the like.
Examples of the "sweetening agent" include sodium saccharin, dipotassium glycyrrhizinate, aspartame, and the like.
The pharmaceutical composition of the present invention can be administered orally or parenterally (eg, topically, rectally, intravenously, etc.) to humans as well as to mammals other than the human being (for example, mouse, rat, hamster, guinea pig, rabbit, cat, dog, pig, cattle, horse, sheep, monkey, etc.). The dose varies according to the subject administration, disease, symptom, dosage form, route of administration and the like. For example, the daily dose for oral administration to an adult patient (body weight: about 60 kg) is generally within the range of about 1 mg to 1 g, based on the compound [I] as the active ingredient. This amount can be administered in one to several portions.
The compound of the present invention has an inhibitory activity of the inducible T cell kinase (ITK). Accordingly, the compound of the present invention can be used as an active ingredient of an agent for the treatment or prophylaxis of inflammatory diseases, an agent for the treatment or prophylaxis of allergic diseases, an agent for the treatment or prophylaxis of autoimmune diseases, an inhibitor of rejection in transplantation and the like.
"Inhibiting ITK" or "having ITK inhibitory activity" is understood to inhibit the function of ITK to eliminate or attenuate activity or to have such activity. For example, it means measuring the inhibitory activity of ITK on the basis of the conditions of Experimental Example 1 mentioned below, and administering a compound having an inhibitory activity in mammalian or even human to inhibit the function of ITK. "Inhibiting ITK" preferably means "inhibiting human ITK". The "ITK inhibitor" is preferably a "human ITK inhibitor".
While the inflammatory disease is not particularly limited, its examples include rheumatoid arthritis, inflammatory bowel disease, and the like.
While the allergic disease is not particularly limited, its examples include atopic dermatitis, asthma, allergic rhinitis, and the like.
While the autoimmune disease is not particularly limited, its examples include rheumatoid arthritis, systemic lupus erythematosus, psoriasis, inflammatory bowel disease, and the like.
The compound of the present invention can be used in combination with one or a plurality of different drugs (hereinafter also referred to as a concomitant drug) according to a method generally employed in the medical field (hereinafter also referred to as combined use).
The period of administration of the compound of the present invention and a concomitant drug is not limited, and they can be administered to a subject of administration as a combination preparation, or both preparations can be administered simultaneously or at intervals determined as individual preparations. In addition, the pharmaceutical composition of the present invention and a concomitant drug can be used in the form of a kit. The dose of the concomitant drug is similar to the dose used clinically and can be selected in an appropriate manner according to the subject of administration, disease, symptom, dosage form, route of administration, time of administration. administration, combination and the like. The concomitant drug administration form is not particularly limited and only the compound of the present invention is required to be combined with a concomitant drug.
Next, an example of the production methods of the compound for practicing the present invention is explained below. However, the production method of the compound of the present invention is not limited thereto.
Even if the corresponding description is not found directly in the following Production Methods, the steps can be modified for the efficient production of the compound, such as introducing a protective group into a functional group with deprotection at a later stage, submitting a functional group as a precursor to each step, followed by conversion to a desired functional group at an appropriate stage, changing the order of the Methods and stages of production, and the like.
The treatment after the reaction in each stage may be conventional, where isolation and purification may be performed as appropriate according to a method appropriately selected from conventional methods such as crystallization, recrystallization, distillation, partitioning, silica gel chromatography , Preparative HPLC, and the like, or a combination of these methods.
Production method 1 [i] wherein R9 and R10 are the same or different and each is an amino protecting group; and the other symbols are as previously defined.
Examples of the "amino protecting group" for R 9 or R 0 include a tert-butoxycarbonyl group, an ethoxycarbonyl group, a trityl group, a tetrahydropyranyl group, a methoxymethyl group, a 2- (trimethylsilyl) ethoxymethyl group, a p-group toluenesulfonyl, and the like, giving preference to a tert-butoxycarbonyl group. (stage 1) The compound [3] can be obtained by subjecting the compound [1] and the compound [2] to the Suzuki coupling reaction. For example, the compound [3] can be obtained by reacting the compound [1] with the compound [2] in a solvent under heating in the presence of a base and a palladium catalyst. The reaction is preferably carried out by gradually adding the compound [2] in the presence of all the other reagents under heating.
Examples of the palladium catalyst for use in the reaction include tetrakistriphenylphosphine palladium, (bis (diphenylphosphino) ferrocene) palladium-methylene chloride dichloride complex, and the like.
Examples of the base to be used in the reaction include potassium phosphate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, triethylamine and the like.
Preferable examples of the solvent for use in the reaction include ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane and the like; alcohol solvents such as methanol, ethanol, n-propanol, isopropanol and the like; hydrocarbon solvents such as toluene, hexane, xylene and the like; polar solvents such as?,? - dimethylformamide, dimethyl sulfoxide, acetonitrile, and the like; and one of its mixed solvents with water.
The compound [1] and the compound [2] can be commercially available products or can be obtained according to the following production methods 2 and 3 or a conventional method. (stage 2) The compound [I] can be obtained by removing R9 and R10 of the compound [3] by means of a general deprotection reaction. The deprotection reaction can be carried out under conditions appropriate for the types or a combination of R9 and R10. For example, when both R9 and R10 are tert-butoxycarbonyl groups, compound [I] can be obtained by treating the compound [3] in a solvent in the presence of a base at room temperature.
Examples of the base to be used in the reaction include sodium hydroxide, lithium hydroxide, sodium carbonate and the like.
Preferable examples of the solvent for use in the reaction include ether solvents such as 1,4-dioxane, tetrahydrofuran and the like; alcohol solvents such as methanol, ethanol, n-propanol, isopropanol and the like; polar solvents such as N, N-dimethylformamide, dimethisulfoxide, acetonitrile and the like; and one of its mixed solvents with water.
Production method 2 where each symbol is as defined previously. (stage 1) The compound [5] can be obtained by reacting the compound [4] with ethyl formate in a solvent in the presence of a base.
Examples of the base to be used in the reaction include sodium hydride, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, lithium diisopropylamide, lithium hexamethyldisilazide and the like.
Preferable examples of the solvent for use in the reaction include ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane and the like; alcohol solvents such as methanol, ethanol, n-propanol, isopropanol and the like; and polar solvents such as?,? - dimethylformamide, dimethyl sulfoxide, acetonitrile and the like.
The compound [4] can be a commercially available product or can be obtained by a conventional method. (stage 2) The compound [6] can be obtained by reacting the compound [5] with hydrazine in a solvent at a temperature from room temperature to under heating. This step is sometimes carried out preferably from room temperature to under heating. In addition, an acid can be used if necessary for the reaction.
Preferable examples of the solvent to be used in the reaction include alcohol solvents such as methanol, ethanol, n-propanol, isopropanol and the like; and polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile and the like.
Examples of the acid to be used in the reaction include hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, p-toluene p-toluenesulfonate and the like. (stage 3) The compound [7] can be obtained by reacting the compound [6] with iodine in a solvent in the presence of a base at a temperature from room temperature to under heating.
Examples of the base to be used in the reaction include potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate and the like.
Preferable examples of the solvent for use in the reaction include ether solvents such as 1,4-dioxane, tetrahydrofuran and the like; alcohol solvents such as methanol, ethanol, n-propanol, isopropanol and the like; polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile and the like; and one of its mixed solvents with water. (stage 4) The compound [1] can be obtained by introducing an amino protecting group (R9) into the compound [7]. For example, when R9 is a tert-butoxycarbonyl group, compound [1] can be obtained by reacting compound [7] with di-tert-butyl dicarbonate in a solvent from room temperature to under heating in the presence of a base.
Examples of the base to be used in the reaction include tertiary amines such as triethylamine, 4-dimethylaminopyridine and the like.
Preferable examples of the solvent for use in the reaction include ether solvents such as 1,4-dioxane, tetrahydrofuran and the like; ester solvents such as ethyl acetate and the like; hydrocarbon solvents such as toluene, hexane, xylene and the like; and polar solvents such as?,? - dimethylformamide, dimethyl sulfoxide, acetonitrile and the like.
Production method 3 where each symbol is as defined previously. (stage 1) The compound [9] can be obtained by introducing an amino protecting group (R10) into the compound [8]. For example, when R10 is a tert-butoxycarbonyl group, compound [9] can be obtained by reacting the compound [8] with di-tert-butyl dicarbonate in a solvent from room temperature to under heating in the presence of a base.
Examples of the base to be used in the reaction include tertiary amines such as 4-dimethylaminopyridine, triethylamine and the like, with preference given to a 4-dimethylaminopyridine.
Preferable examples of the solvent for use in the reaction include ether solvents such as 1,4-dioxane, tetrahydrofuran and the like; ester solvents such as ethyl acetate and the like; hydrocarbon solvents such as toluene, hexane, xylene and the like; and polar solvents such as?,? - dimethylformamide, dimethyl sulfoxide, acetonitrile and the like.
The compound [8] can be a commercially available product or can be obtained by a conventional method. (stage 2) The compound [2] can be obtained by reacting the compound [9] with borate in a solvent under cooling in the presence of a base. The reaction is preferably carried out by gradually adding dropwise a base under cooling in the presence of borate.
Examples of the borate for use in the reaction include triisopropylborate, trimethylborate and the like.
Examples of the base to be used in the reaction include butyllithium, lithium diisopropylamide, lithium hexamethyldisilazide and the like.
Preferable examples of the solvent for use in the reaction include ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, and the like.
The compound [1-b], which is the compound [I] wherein R 4 is a group represented by which is attached to the 5-position or the 6-position of the indole ring, can also be produced according to the following production method 4 or 7.
Production method 4 [1 i] [I-b] wherein R 1 is a carboxy protecting group; and the other symbols are as previously defined.
Examples of the "carboxy protecting group" for R 11 include an alkyl group such as a methyl group, an ethyl group, a tert-butyl group, and the like, a tert-butyldimethylsilyl group, a benzyl group, a methoxyethoxymethyl group, and the like . (stage 1) The compound [10] can be obtained in the same manner as in the production method 1, from the compound [1] and the compound [2-1] obtained in the same manner as in production method 3. (stage 2) The compound [11] can be obtained by removing R1 from compound [10] by means of a deprotection reaction. The deprotection reaction can be carried out under conditions appropriate for the type of R11. For example, when R is an alkyl group, the compound [11] can be obtained by hydrolyzing the compound [10] in a solvent in the presence of a base at a temperature from room temperature to under heating and acidifying the obtained solution.
Examples of the base to be used in the reaction include potassium carbonate, sodium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydride, sodium hydride, potassium hydride and the like.
Preferable examples of the solvent for use in the reaction include a mixed solvent of water with alcohol solvents such as methanol, ethanol, n-propanol, isopropanol and the like; and one of its mixed solvents with ether solvents such as 1,4-dioxane, tetrahydrofuran and the like. (stage 3) The compound [1-b] can be obtained by reacting the compound [11] with amine [12] in a solvent in the presence of a condensing agent at a temperature of cooling to heating. An activator can be used to gently carry out the reaction.
Examples of the condensation agent to be used in the reaction include N, N'-carbonyldiimidazole,?,? '-dicyclohexylcarbodiimide,?,?' -diisopropylcarbodiimide, 1- ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride ( EDC) and similar.
Examples of the activator to be used in the reaction include hydroxysuccinimide, 1-hydroxybenzotriazole and the like.
Preferable examples of the solvent for use in the reaction include hydrocarbon solvents such as benzene, toluene, hexane, xylene and the like; halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran and the like; polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile and the like; pyridine; and one of its mixed solvents.
The amine [12] can be an affordable product in shops or can be obtained by a conventional method.
The compound [1-c], which is the compound [I] wherein R 4 is a group represented by which is attached to position 5 or position 6 of the indole ring, can also be produced by means of the following production method 5 or 6.
Production method 5 wherein R 12 is an amino protecting group; R 13 is an alkyl group such as a methyl group, an ethyl group, a tert-butyl group, and the like, a benzyl group, and the like; and the other symbols are as previously defined.
Examples of the "amino protecting group" for R 2 include a 2- (trimethylsilyl) ethoxymethyl group, a trityl group, a tetrahydropyranyl group, a methoxymethyl group, a p-toluenesulfonyl group, and the like, giving preference to a group 2- (trimethylsilyl) ethoxymethyl. (stage 1) The compound [13] can be obtained by introducing an amino protecting group (R 2) into the compound [10]. For example, when R12 is a 2- (trimethylsilyl) ethoxymethyl group, compound [13] can be obtained by reacting compound [10] with 2- (trimethylsilyl) ethoxymethyl chloride in a solvent under cooling in the presence of a base.
Examples of the base to be used in the reaction include sodium hydride and the like.
Examples of the solvent to be used in the reaction include ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran and the like; and polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile and the like. (stage 2) The compound [14] can be obtained by removing R11 from the compound [13]. The reaction can be carried out in the same manner as in step 2 of the production method 4. (stage 3) The compound [15] can be obtained by subjecting the compound [14] to the rearrangement of Curtius with diphenylphosphorylazide to give the corresponding isocyanate and react the isocyanate obtained with the corresponding alcohol (R13OH). The rearrangement of Curtius can also be carried out by reacting the acid chloride of the compound [14] with sodium azide to produce the corresponding acid azide, followed by heating. When alcohol (R13OH) is present in the rearrangement of Curtius, the isocyanate is reacted immediately with alcohol to give the compound [15]. For example, when R13 is a benzyl group, compound [15] can be obtained by reacting compound [14] by dropwise addition of diphenylphosphorylazide in a solvent under heating in the presence of benzyl alcohol and a tertiary amine.
Examples of the tertiary amine to be used in the reaction include triethylamine and the like.
Preferable examples of the solvent for use in the reaction include hydrocarbon solvents such as benzene, toluene, hexane, xylene and the like; and ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, and the like. (stage 4) When R7 is not a hydrogen atom, the compound [16] can be obtained by introducing R7 by reacting the compound [15] with a corresponding alkylating agent in a solvent under cooling with ice to room temperature in the presence of a base.
The alkylating agent to be used in the reaction can be any as long as it can introduce R7 and its examples include methyl iodide, ethyl iodide, benzyloxymethane chloride and the like.
Examples of the base to be used in the reaction include sodium hydride, butyl lithium, lithium diisopropylamide, lithium hexamethyldisilazide and the like.
Preferable examples of the solvent for use in the reaction include hydrocarbon solvents such as benzene, toluene, hexane, xylene and the like; ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran and the like; and polar solvents such as?,? - dimethylformamide, dimethyl sulfoxide, acetonitrile and the like.
When R7 is a hydrogen atom, the compound [15] can be directly subjected to step 5 without performing step 4. (stage 5) The compound [17] can be obtained by reducing the compound [16] by means of a conventional method. For example, when R13 is a benzyl group, the compound [17] can be obtained by a conventional method such as catalytic reduction, and the like. The catalytic reduction can be carried out, for example, in a solvent in the presence of a metal catalyst from room temperature to heating under normal pressure to under pressurization and using a hydrogen gas. As a hydrogen source, ammonium formate, cyclohexene, dicyclohexene and the like can be used.
Examples of the metal catalyst for use in the reaction include palladium on carbon, palladium hydroxide, palladium black, Raney nickel and the like.
Preferable examples of the solvent to be used in the reaction include alcohol solvents such as methanol, ethanol, n-propanol, isopropanol and the like; ether solvents such as 1,4-dioxane, tetrahydrofuran and the like; ester solvents such as ethyl acetate and the like; and one of its mixed solvents. (stage 6) The compound [19] can be obtained by condensation of the compound [17] with the compound [18] according to an amide condensation method used in general. For example, the compound [18] is treated with a halogenating agent in a solvent at room temperature to give the corresponding acid halide. Then, the acid halide obtained is condensed with the compound [17] in the presence of a tertiary amine or pyridine from cooling to room temperature to give the compound [19].
Examples of the halogenating agent to be used in the reaction include oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride and the like.
Examples of the tertiary amine to be used in the reaction include triethylamine and the like.
Preferable examples of the solvent for use in the reaction include halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran and the like; and one of its mixed solvents with water.
The compound [18] can be a commercially available product or can be obtained according to a conventional method. When the corresponding acid halide is available in shops, it can also be used.
In addition, the compound [19] can also be obtained by condensation of the compound [17] and the compound [18] in the same manner as in step 3 of the production method 4. (stage 7) The compound [l-c] can be obtained by eliminating R12 from compound [19] by means of a deprotection reaction. The deprotection reaction can be carried out using conditions appropriate for the type of R12. For example, when R 12 is a 2- (trimethylsilyl) ethoxymethyl group, the compound [1-c] can be obtained by reacting the compound [19] in a solvent under heating in the presence of tetrabutylammonium fluoride and ethylenediamine.
Preferable examples of the solvent for use in the reaction include ether solvents such as 1,4-dioxane, tetrahydrofuran and the like; and polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile and the like. where each symbol is as defined previously, (stage 1) The compound [20] can be obtained by removing R 2 from the compound [16] obtained in step 4 of the production method 5. The reaction can be carried out in the same manner as in step 7 of the production method 5. (stage 2) The compound [21] can be obtained by subjecting the compound [20] to a reduction reaction. The reaction can be carried out in the same manner as in step 5 of the production method 5. (stage 3) The compound [22] can be obtained by condensation of the compound [21] and the compound [18]. The reaction can be carried out in the same manner as in step 6 of the production method 5.
Alternatively, the compound [1-c] is sometimes obtained directly by means of the aforesaid reaction without performing step 4. (stage 4) The compound [1-c] can be obtained from the compound [22] by removing an acyl group in the pyrazole ring. For example, the compound [1-c] can be obtained by hydrolyzing the compound [22] in a solvent from room temperature to heating in the presence of a base.
Examples of the base to be used in the reaction include potassium carbonate, sodium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydride, sodium hydride, potassium hydride and the like. Examples of the solvent to be used in the reaction include aqueous alcohol solvents such as methanol, ethanol, n-propanol, isopropanol and the like; and one of its mixed solvents with ether solvents such as 1,4-dioxane, tetrahydrofuran and the like.
Production method 7 (stage 1) The compound [24] can be obtained by condensation of the compound [14] obtained in step 2 of the production method 5 with amine [23]. The reaction can be carried out in the same manner as in step 3 of the production method 4. (stage 2) The compound [25] can be obtained by reacting the compound [23] with the corresponding alkylating agent to introduce R5. The reaction can be carried out in the same manner as in step 4 of the production method 5. (stage 3) The compound [1-b] can be obtained by removing R 2 from compound [25] by means of a deprotection reaction. The reaction can be carried out in the same manner as in step 7 of the production method 5.
EXAMPLES The present invention is explained below in detail with reference to Reference Examples, Examples and Experimental Example, which are not constructed as limiting.
The ambient temperature in the Reference Examples and the Examples involves 1-40 ° C.
REFERENCE EXAMPLE 1 Production of tert-butyl 3-iodo-6,6-dimethyl-4,5,6,7-tetrahydroindazole-1-carboxylate (stage 1 ) Production of 3-iodo-6,6-dimethyl-4,5,6,7-tetrahydro-1 H-indazole Under a nitrogen atmosphere, to a suspension of sodium hydride (28 g, 697 mmol) in tetrahydrofuran (500 mL) was added dropwise a solution of 3,3-dimethylcyclohexanone (80 g, 634 mmol) in tetrahydrofuran (250 mi) under cooling with ice for about 1 h and the mixture was stirred for 1 h. Next, a solution of ethyl formate (99 g, 1.3 mole) in tetrahydrofuran (250 ml) was added dropwise over about 1 h and the mixture was stirred under ice-cooling for 1 h and at room temperature for 1 h. Water and ethyl acetate were added to the reaction mixture and the organic layer was separated and extracted with 2N aqueous sodium hydroxide solution. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. Then, the organic layer was washed with saturated brine and dried over sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure to give 4,4-dimethyl-2-oxocyclohexanecarbaldehyde. To a solution of 4,4-dimethyl-2- oxocyclohexanecarbaldehyde obtained in methanol (376 ml) was added dropwise a solution of hydrazine monohydrate (31 ml, 640 mmol) in methanol (31 ml) with heating under reflux for about 1 h and the mixture was stirred for 15 min. The reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added and the organic layer was separated. Then, the organic layer was washed with saturated brine and dried over sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure to give 6,6-dimethyl-4,5,6,7-tetrahydro-1 H-indazole. To a solution of 6,6-dimethyl-4,5,6,7-tetrahydro-1 H-indazole obtained in N, N-dimethylformamide (1.4 L) were added iodine (232 g, 915 mmol) and potassium (121 g, 1.8 mole) at room temperature and the mixture was stirred for about 4 h. Then, under cooling with ice, an aqueous solution (800 ml) of sodium hydrogen sulfite (80 g) was added dropwise. Water (2 L) was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure. Next, the hexane (350 ml) was added to the residue and the mixture was stirred at room temperature. The precipitated crystals were collected by filtration, washed with hexane and dried under reduced pressure to give 3-iodo-6,6-dimethyl-4,5,6,7-tetrahydro-1 H-indazole (41 g, yield 23). %). 1 H-NMR (400MHz, DMSO-d 6) d: 0.94 (s, 6H), 1.47 (t, 2H, J = 6.38 Hz), 2.21 (t, 2H, J = 6.38 Hz), 2.33 (s, 2H), 12.69 (s, 1 H). (stage 2) Production of 3-vodo-6,6-dimethyl-4,5,6,7-tetrahydroindazole-1-carboxylate of tert-butyl To a solution of 3-iodo-6,6-dimethyl-4,5,6,7-tetrahydro-1 H-indazole (41 g, 147 mmol), triethylamine (22 mL, 155 mmol) and 4-dimethylaminopyridine (824) mg, 7 mmol) in tetrahydrofuran (163 ml) was added dropwise a solution of di-tert-butyl dicarbonate (34 g, 155 mmol) in tetrahydrofuran (41 ml) at room temperature for 40 min and the mixture was stirred for 30 min. Then, the reaction mixture was concentrated under reduced pressure. The residue was washed in suspension in hexane (130 ml) at 60 ° C and cooled on ice. The crystals were collected by filtration, washed with hexane and dried under reduced pressure to give the title compound (53 g, 95% yield).
H-NMR (400MHz, DMSO-d6) d: 0.95 (s, 6H), 1.46 (t, 2H, J = 6. 38 Hz), 1.56 (s, 9H), 2.23 (t, 2H, J = 6.26 Hz), 2.63 (s, 2H).
REFERENCE EXAMPLE 2 Production of 1-tert-butyl 6-methyl 2-boronylindole-1,6-dicarboxylate (stage 1 ) Production of 1 H-indole-6-carboxylate methyl Under a nitrogen atmosphere, to a solution of 1 H -indole-6-carboxylic acid (121 g, 752 mmol) in N, N-dimethylformamide (360 mL) was added potassium carbonate (124 g, 900 mmol) and The mixture was stirred at room temperature for 1 h. Then, the iodomethane (56 ml, 900 mmol) was added dropwise at room temperature for 15 min and the mixture was stirred for 2 h. Then, water (1.2 L) and hexane (100 ml) were added to the reaction solution and the mixture was stirred at room temperature for 1 h. The precipitated crystals were collected by filtration, washed successively with water and hexane and dried under reduced pressure to give the title compound (15 g, 87% yield).
H-NMR (400MHz, DMSO-d6) d: 3.85 (3H, s), 6.53 (1 H, d, J = 1.61 Hz), 7.60-7.63 (3H, m), 8.07 (1 H, s), 1 1.48 (1 H, s). (stage 2) Production of 1-tert-butyl 6-methyl indole-1, 6-dicarboxylate To a solution of 1 H -indole-6-carboxylic acid methyl ester (124 g, 708 mmol) in tetrahydrofuran (500 mL) was added 4-dimethylaminopyridine (865 mg, 7 mmol). Next, a solution of di-carbonate dicarbonate. Butyl (156 g, 715 mmol) in tetrahydrofuran (150 ml) was added dropwise at room temperature for about 1 h and the mixture was stirred for 1 h. The reaction mixture was concentrated and the residue was purified by chromatography on silica gel to give the title compound (193 g, 99% yield). 1 H-NMR (400MHz, DMSO-d 6) d: 1.65 (9H, s), 3.89 (3H, s), 6.82 (1H, dd, J = 3.63, 0.86 Hz), 7.74 (1H, d, J = 8.06 Hz ), 7.85 (1H, dd, J = 8.06, 0.86 Hz), 7.87 (1 H, d, J = 3.63 Hz), 8.76 (1H, d, J = 0.81 Hz). (stage 3) Production of 1-tert-butyl 6-methyl 2-boronylindole-1,6-dicarboxylate To a solution of 1-tert-butyl 6-methyl indole-6-dicarboxylate (107 g, 389 mmol) in tetrahydrofuran (135 mL) was added triisopropylborate (135 mL, 584 mmol) and the internal temperature was cooled to -5 ° C. Next, a solution (253 mL, 506 mmol) of lithium diisopropylamide in hexane was added dropwise over 1.5 h while maintaining the internal temperature at -5 ° C or less and the mixture was further stirred for 1 h. Then, 10% aqueous solution of citric acid (1.2 L) was added dropwise to the reaction solution under cooling with ice. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine and dried over magnesium sulfate. The magnesium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was washed in suspension with a mixed solvent of ethyl acetate (333 ml) and hexane (666 ml) and the precipitate was collected by filtration, washed with hexane and dried under reduced pressure to give the title compound (73 g, 59% yield). 1 H-NMR (400MHz, DMSO-d 6) d: 1.62 (s, 9H), 3.88 (s, 3H), 6.72. (d, 1 H, J = 0.88 Hz), 7.68 (t, 1 H, J = 4.08 Hz), 7.82 (dd, 1 H, J = 8.16, 1.54 Hz), 8.33 (s, 2H), 8.78 (t , 1 H, J = 0.77 Hz).
REFERENCE EXAMPLE 3 Production of (S) -2- (morpholin-4-yl) propionic acid (stage 1) Production of (S) -2- (morpholin-4-yl) benzyl propionate Under an argon atmosphere, a solution of L-alanine benzyl ester tosylate (3.4 g, 9.7 mmol) and triethylamine (6.8 ml) in dimethyl sulfoxide (17 ml) was added a solution of 1-bromo-2- (2 -bromoethoxy) ethane (1.5 ml, 12 mmol) in dimethylsulfoxide (3 ml) under cooling with ice and the mixture was stirred at room temperature for 24 h. Water and ethyl acetate were added to the reaction solution and the organic layer was separated. Then, the organic layer was washed with saturated brine and dried over sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel to give the title compound (1.6 g, 64% yield). 1 H-NMR (400MHz, DMSO-d 6) d: 1.20 (d, 3H, J = 7.25 Hz), 2.44- 2. 59 (m, 4H), 3.35 (q, 1 H, J = 7.25 Hz), 3.47-3.59 (m, 4H), 5.16-5.09 (m, 2H), 7.29-7.40 (m, 5H). (stage 2) Production of (S) -2- (morpholin-4-yl) propionic acid Under an argon atmosphere, to a solution of benzyl (S) -2- (morpholin-4-yl) propionate (43 g, 172 mmol) in methanol (430 ml) was added 20% palladium hydroxide on carbon ( 4.3 g) at room temperature and the mixture was stirred for 3 h under an atmosphere of hydrogen at normal pressure. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give the title compound (25.4 g, 93%). 1 H-NMR (400MHz, DMSO-d 6) d: 1.17 (d, 3H, J = 6.98 Hz), 2.47- 2.63 (m, 4H), 3.17 (q, 1 H, J = 6.98 Hz), 3.50-3.63 ( m, 4H).
REFERENCE EXAMPLE 4 Production of (3-oxomorpholin-4-yl) acetic acid Production of 2-chloro-N- (2-hydroxyethyl) acetamide Under an atmosphere of argon, to a solution of 2-aminoethanol (5 g, 82 mmol) and triethylamine (1.4 mL, 82 mmol) in tetrahydrofuran (60 mL) was added dropwise chloroacetyl chloride (6.2 mL, 78 mmol. ) under cooling with ice for 30 min and the mixture was stirred for 1 h. The reaction mixture was then stirred at room temperature for 3 h and dried over magnesium sulfate. The magnesium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel to give the title compound (3.2 g, yield 30%). 1 H-NMR (400 MHz, DMSO-d 6) d: 3.16 (q, 2 H, J = 5.87 Hz), 3.42 (q, 2 H, J = 5.87 Hz), 4.06 (s, 2 H), 4.71 (t, 1 H, J = 5.45 Hz), 8.18 (s, 1 H). (stage 2) Production of morpholin-3-one Under an atmosphere of argon, to a solution of 2-chloro-N- (2-hydroxyethyl) acetamide (3.2 g, 23 mmol) in tetrahydrofuran (64 ml) was added sodium hydride (1.2 g, 30 mmol) under cooling with ice and the mixture was stirred for 1 h. The mixture was then stirred at room temperature for 1 h and then at 60 ° C for 4 h. After cooling, water (540 μl) was added and the reaction mixture was dried over magnesium sulfate. The magnesium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel to give the title compound (232 mg, 10% yield).
H-NMR (400MH z, DMSO-d6) d: 3.20-3.23 (m, 2H), 3.70-3.73 (m, 2H), 3.96 (s, 2H), 7.88-8.07 (brs, 1H). (stage 3) Production of benzyl (3-oxomorpholin-4-yl) acetate Under an atmosphere of argon, to a solution of morpholin-3-one (220 mg, 2.2 mmol) in N, N-dimethylformamide (2.2 ml) was added sodium hydride (105 mg, 2.6 mmol) under ice-cooling and the The mixture was stirred for 1 h. Then, benzyl bromoacetate (379 μl, 2.4 mmol) was added and the mixture was stirred for 2 h. Water and ethyl acetate were added to the reaction solution and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were washed successively with water and saturated brine and dried over sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel to give the title compound (321 mg, yield 59%). 1 H-NMR (400MHz, DMSO-d 6) d: 3.40-3.43 (m, 2H), 3.83-3.85 (m, 2H), 4.08 (s, 2H), 4.21 (s, 2H), 5.16 (s, 2H) , 7.32-7.41 (m, 5H). (stage 4) Production of (3-oxomorpholinyl) -acetic acid Under an argon atmosphere, to a solution of benzyl (3-oxomorpholin-4-yl) acetate (319 mg, 1.3 mmol) in methanol (5 ml) was added 20% palladium hydroxide on carbon (64 mg) at room temperature. The mixture was then stirred for 2 h under an atmosphere of hydrogen at normal pressure. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give the title compound (206 mg, yield by weight). 1 H-NMR (400MHz, DMSO-d 6) d: 3.37-3.40 (m, 2H), 3.82-3.84 (m, 2H), 4.03 (s, 2H), 4.06 (s, 2H), 12.22-13.57 (brs, 1 HOUR).
REFERENCE EXAMPLE 5 Production of 6-benzyloxymethyl-3-iodo-6-methyl-4,5,6,7-tetrahydroindazole-1-carboxylate of tert-butyl (stage 1) Production of 7-methyl-1,4-dioxaespiro [4,51decan-8-one] Under a nitrogen atmosphere, to a solution of lithium bis (trimethylsilyl) amide (1 M, 100 mL, 100 mmol) in tetrahydrofuran (200 mL) was added dropwise a solution of 1,4-dioxaspiro [4.5 ] decan-8-one (15.6 g, 100 mmol) in tetrahydrofuran (50 ml) at -78 ° C for about 30 min and the mixture was stirred for 30 min. Then, methyl iodide (2.5 ml, 120 mmol) was added dropwise over 5 min and the mixture was stirred at -78 ° C for 30 min and at room temperature for 2 h. To the reaction mixture was added saturated aqueous solution of ammonium chloride and the mixture was extracted three times with diethyl ether. The combined organic layers were dried over magnesium sulfate. The magnesium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel to give the title compound (10.6 g, 62% yield). 1 H-NMR (400MHz, DMSO-d 6) d: 0.90 (3H, d, J = 6.62 Hz), 1.65 (1H, t, J = 13.01 Hz), 1.84-2.04 (3H, m), 2.19 (1 H, ddd, J = 14.50, 5.13, 3.03 Hz), 2.49-2.69 (2H, m), 3.85 ^ .06 (4H, m). (stage 2) Production of 7-hydroxymethyl-7-methyl-1, 4-dioxa-spiro [4,5-decan-8-one] 7-Methyl-1,4-dioxaespiro [4.5] decan-8-one (10.5 g, 62 mmol) was dissolved in a methanolic solution of potassium hydroxide (10% w / w, 60 g). To the solution was added dropwise a solution of aqueous formaldehyde solution (37%, 4.6 ml) in methanol (5 ml) under ice-cooling for 20 min and the mixture was stirred for 30 min. Then, 1 N hydrochloric acid and aqueous solution were added to the reaction mixture. saturated ammonium chloride and the mixture was extracted three times with chloroform. The combined organic layers were dried over magnesium sulfate. The magnesium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel to give the title compound (6.9 g, 56% yield). 1 H-NMR (400MHz, DMSO-d 6) d: 0.98 (3H, s), 1.67 (1 H, dd, J = 14.00, 1.41 Hz), 1.86-1.97 (2H, m), 2.08 (1H, dd, J = 14.00, 1.61 Hz), 2.33-2.48 (2H, m), 3.42-3.50 (2H, m), 3.90-3.95 (4H, m), 4.63 (1 H, t, J = 5.24 Hz). (stage 3) Production of (7-methyl-1,4-dioxaespiro [4.5ldeca-7-yl] methanol) To a solution of 7-hydroxymethyl-7-methyl-1,4-dioxaespiro [4.5] decan-8-one (6.9 g, 65 mmol) in methanol (40 mL) was added p-toluenesulfonyl hydrazide (7.4 g, 40 mmol) and the mixture was heated to reflux for 3 h. Then, to the reaction solution were added methanol (120 ml), sodium cyanoborohydride (2.9 g, 46 mmol) and a solution (100 ml) of zinc chloride (3.1 g, 23 mmol) in methanol and the mixture was added. heated at reflux for 2 h. After cooling, 1 N aqueous sodium hydroxide solution (700 ml) was added, the mixture was filtered through celite and the filtrate was extracted three times with ethyl acetate. The combined organic layers were washed successively with water and saturated brine and dried over sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel to give the title compound (4.0 g, 61% yield).
H-NMR (400MHz, DMSO-d6) d: 0.96 (3H, s), 1.18-1.87 (8H, m), 3.18 (1 H, d, J = 8.06 Hz), 3.35 (1 H, dd, J = 10.88, 6.45 Hz), 3.51 (1 H, dd, J = 10.88, 9.07 Hz), 3.93-3.94 (4H, m). (stage 4) Production of 7-benzyloxymethyl-7-methyl-1,4-dioxaespiro [4.51decano Under a nitrogen atmosphere, to a solution of (7-methyl-1,4-dioxaespiro [4.5] deca-7-yl) methanol (4.0 g, 21 mmol) in N, N-dimethylformamide (40 mL) was added hydride of sodium (1.1 g, 27 mmol) under cooling with ice and the mixture was stirred for 30 min. Then, benzyl bromide (3.1 ml, 25 mmol) was added to the reaction mixture at room temperature and the mixture was stirred for 1 h. Diethyl ether and water were added to the reaction mixture and the organic layer was separated. Then, the organic layer was washed successively with water and saturated brine and dried over sodium sulfate. Sodium sulfate was eliminated by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel to give the title compound (5.7 g, yield 93%). 1 H-NMR (400MHz, DMSO-d 6) d: 0.95 (3H, s), 1.14-1.19 (1 H, m), 1.32-1.59 (7H, m), 3.20 (2H, dd, J = 28.41, 8.66 Hz ), 3.77-3.85 (4H, m), 4.45 (2H, s), 7.29-7.33 (5H, m). (stage 5) Production of 3-benzyloxymethyl-3-methylcyclohexanone To a solution of 7-benzyloxymethyl-7-methyl-1,4-dioxaespiro [4.5] decane (5.3 g, 19 mmol) in a mixed solvent of acetone (42 ml) and water (11 ml) was added p pyridinium toluene sulfonate (4.8 g, 19 mmol) and the mixture was stirred with heating at 80 ° C for 2 h. After cooling, ethyl acetate and water were added to the reaction mixture and the organic layer was separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed successively with water and saturated brine and dried over sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel to give the title compound (3.9 g, 88% yield).
H-NMR (400MHz, DMSO-d6) d: 0.88 (3H, s), 1.43-1.49 (1 H, m), 1.72-1.84 (3H, m), 2.01 (1 H, dt, J = 13.67, 1.43 Hz), 2.17-2.26 (2H, m), 2.32 (1 H, d, J = 13.45 Hz), 3.17 (2H, dd, J = 10.81, 8.82 Hz), 4.47 (2H, s), 7.26-7.38 ( 5H, m). (stage 6) Production of 6-benzyloxymethyl-3-vodo-6-methyl-4,5,6,7-tetrahydroindazole-1-carboxylate of tert-butyl In the same manner as in Reference Example 1, the title compound (3.8 g) was obtained from 3-benzyloxymethyl-3-methylcyclohexanone (3.9 g).
REFERENCE EXAMPLE 6 Production of (2-oxopiperidin-1-yl) acetic acid (stage 1 ) Production of benzyl (2-oxopiperidin-1-yl) acetate Under a nitrogen atmosphere, to a solution of piperidin-2-one (9.8 g, 99 mmol) in N, N-dimethylformamide (100 ml) was added sodium hydride (4.4 g, 10 mmol) under ice-cooling and the mixture was stirred for 1 h. Then, benzyl bromoacetate (19 ml, 120 mmol) was added and the mixture was further stirred for 2 h. To the reaction mixture were added ethyl acetate and water and the organic layer was separated, washed successively with water and saturated brine and dried over sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel to give the title compound (6.0 g, 24% yield). 1 H-NMR (400MHz, DMSO-d 6) d: 1.62-1.66 (4H, m), 2.1 1 (2H, t, J = 6.45 Hz), 3.10-3.12 (2H, m), 4.21 (2H, s), 5.18 (2H, s), 7.21-7.40 (5H, m). (stage 2) Production of (2-oxopiperidin-1-yl) acetic acid Under a nitrogen atmosphere, to a solution of benzyl (2-oxopiperidin-1-yl) acetate (6.0 g, 24 mmol) in methanol (60 mL) was added 20% palladium hydroxide on carbon (400 mg) Room temperature and the mixture was stirred for 4 h under an atmosphere of hydrogen at normal pressure. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give the title compound (4.0 g, yield by weight).
H-NMR (400MHz, DMSO-d6) d: 1.71-1.74 (4H, m), 2.23 (2H, t, J = 6.04 Hz), 3.17-3.31 (2H, m), 3.94 (2H, s), 12.58 (1 H, s).
EXAMPLE 1 Production of N-r2- (6,6-dimethyl'4.5.6.7-tetrahydro-1 H-indazol-3-iQ- (stage 1 ) Production of 2- (1-tert-butoxycarbonyl-6,6-dimethyl-4,5,6,7-tetrahydro-1 H-indazol-3-yl) -dol-1,6-dicarboxylate of 1-tert-butyl 6- methyl Under an argon atmosphere, to a solution of tert-butyl 3-iodo-6,6-dimethyl-4,5,6,7-tetrahydroindazole-1-carboxylate obtained in Reference Example 1 (49 g, 130 mmol ), potassium phosphate (110 g, 520 mmol) and (bis (diphenylphosphino) ferrocene) palladium-methylene chloride (1 g, 13 mmol) dichloride complex in a mixed solvent of 1,4-dioxane (780 ml) ) and water (330 ml) was added 1-tert-butyl 6-methyl 2-boronylindole-1,6-dicarboxylate (42 g, 130 mmol) obtained in Reference Example 2 in 2 g portions with heating to 110 C for 15 min and the mixture was stirred for 5 min. After cooling, water and ethyl acetate were added to the reaction mixture and the organic layer was separated. Next, the organic layer was washed successively with water and saturated brine and dried over sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel to give the title compound (40 g, 58% yield). 1 H-NMR (400MHz, DMSO-d 6) d: 1.01 (s, 6H), 1.40 (s, 9H), 1.48 (t, 2H, J = 6.15 Hz), 1.57 (s, 9H), 2.41 (t , 2H, J = 5.80 Hz), 2.72 (s, 2H), 3.90 (s, 3H), 7.06 (s, 1 H), 7.77 (d, 1H, J = 8.35 Hz), 7.89 (dd, 1 H, J = 8.35, 1.16 Hz), 8.73 (t, 1 H, J = 0.70 Hz). (stage 2) Production of 2- (6,6-Dimethyl, 5,6,7-tetrahydro-1 H-indazol-3-yl) -dol-6-carboxylic acid methyl ester To a solution of 2- (1-tert-butoxycarbonyl-6,6-dimethyl-4,5,6,7-tetrahydro-1 H-indazol-3-yl) indole-1,6-dicarboxylate of 1-ter- butyl 6-methyl (39 g, 75 mmol) in a mixed solvent of methanol (180 mL) and tetrahydrofuran (120 mL) was added dropwise 2N aqueous solution of sodium hydroxide (149 mL, 298 mmol) under cooling with ice for 15 min and the mixture was stirred for 15 min. Next, 1 N hydrochloric acid was added dropwise to adjust the pH to 5. The precipitated crystals were collected by filtration, washed with water and dried under reduced pressure to give the title compound (23 g, 97% yield).
H-NMR (400MHz, DMSO-d6) 5: 1.01 (s, 6H), 1.58 (t, 2H, J = 6.38 Hz), 2.42 (s, 2H), 2.68 (t, 2H, J = 6.15 Hz), 3.85 (s, 3H), 6.67 (s, 1 H), 7.59 (s, 2H), 8.07 (s, 1 H), 11.71 (s, 1 H), 12.66 (s, 1H). (stage 3) Production of 2-. { 6,6-dimethyl-1-f2- (trimethylsilyl) ethoxymethyl-4,5,6,7-tetrahydro-1 H -indazol-3-yl 1-yl- (trimethylsilyl) ethoxymethin-1 H -indole-6-carboxylate of methyl Under an argon atmosphere, to a solution of methyl 2- (6,6-dimethyl-4,5,6,7-tetrahydro-1 H -indazol-3-yl) indole-6-carboxylate (23 g, mmol) in N, N-dimethylformamide (230 ml) was added sodium hydride (6.3 g, 157 mmol) in portions of about 500 mg at an internal temperature of -10 ° C and the mixture was stirred for 30 min. Next, the 2- (trimethylsilyl) ethoxymethyl chloride (26 g, 157 mmol) was added dropwise over 15 min and the mixture was stirred for 2 h. To the reaction mixture were added ethyl acetate and water and the organic layer was separated. Then, the organic layer was washed successively with water and saturated brine and dried over sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel to give the title compound (33 g, 80% yield). 1 H-NMR (400MHz, DMSO-d 6) d: -0.21 (s, 9H), -0.03 (s, 9H), 0.68 (t, 2H, J = 8.00 Hz), 0.87 (t, 2H, J = 8.12 Hz ), 1.03 (s, 6H), 1.54 (t, 2H, J = 6.26 Hz), 2.50 (s, 2H), 2.63 (t, 2H, J = 6.26 Hz), 3.30-3.31 (m, 2H), 3.59 (t, 2H, J = 8.00 Hz), 3.87 (s, 3H), 5.42 (s, 2H), 6.14 (s, 2H), 6.83 (d, 1 H, J = 0.70 Hz), 7.67-7.72 (m , 2H), 8.22 (s, 1 H). (stage 4) Acid production 2-. { 6,6-dimethyl-1-f2- (trimethylsilyl) ethoxymethyl] -4.5.6J-tetrahydro-1 H -indazol-3-yl) -1-r2- (trimethylsilyl) ethoxymethin-1H-indole- 6-carboxylic To a solution of 2-. { 6,6-dimethyl-1- [2- (trimethylsilyl) ethoxymethyl] -4,5,67-tetrahydro-1 H -indazol-3-yl} [1- (Methyl 2- (trimethylsilyl) ethoxymethyl] -1H-indole-6-carboxylate (33 g, 57 mmol) in a mixed solvent of tetrahydrofuran (165 mL) and methanol (165 mL) was added 4N aqueous solution of sodium hydroxide (71 ml, 284 mmol) and the mixture was heated at 60 ° C for 2 h. After cooling, the reaction mixture was concentrated, 10% aqueous solution of citric acid was added to the residue to adjust the pH to 5 and the mixture was extracted with ethyl acetate. Then, the organic layer was washed with saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound (31 g, 97% yield). 1 H-NMR (400MHz, DMSO-d 6) d: -0.21 / -0.20 (m, 9H), -0.05 / - 0. 03 (m, 9H), 0.68-0.71 (m, 2H), 0.85-0.91 (m, 2H), 1.03 (s, 6H), 1.54 (t, 2H, J = 6.06 Hz), 2.63 (t, 2H, J = 5.95 Hz), 3.57-3.61 (m, 2H), 5.42 (s, 2H), 6.13 (d, 2H, J = 3.53 Hz), 6.82 (t, 1 H, J = 3.42 Hz), 7.65 -7.70 (m, 2H), 8.20 (s, 1H). (stage 5) Production of (2-f6.6-dimethyl-1- [2- (trimethylsilyl) ethoxymethin-4.5.6 J-tetrahydro-1 H -indazol-3-yl 1-f2- (trimethylsilyl) ethoxymethin-1 H- Benzyl indol-6-iDcarbamate Under an atmosphere of argon, to a solution of 2- acid. { 6,6-dimethyl-1- [2- (trimethylsilyl) ethoxymethyl] -4,5,6,7 ^ (trimethylsilyl) ethoxymethyl] -1H-indole-6-carboxylic acid (26 g, 45 mmol), triethylamine (8.2 mL, 59 mmol) and benzyl alcohol (18 mL, 180 mmol) in toluene (260 mL) was added dropwise Diphenylphosphorylazide drop (12 mL, 54 mmol) at 115 ° C for 2 h. After cooling, water was added to the reaction mixture and the organic layer was separated. Next, the organic layer was washed successively with water and saturated brine and dried over magnesium sulfate. The magnesium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel and washed in suspension in hexane (210 ml) with heating at 60 ° C. The resulting crystals were collected by filtration, washed with hexane and dried under reduced pressure to give the title compound (28 g, 91% yield). 1 H-NMR (400MHz, DMSO-d 6) d: -0.19 (s, 9H), -0.03 (s, 9H), 0. 69 (t, 2H, J = 8.16 Hz), 0.86 (t, 2H, J = 8.05 Hz), 1.02 (s, 6H), 1.52 (t, 2H, J = 6.18 Hz), 2.59 (t, 2H, J = 6.06 Hz), 3.58 (t, 2H, J = 8.05 Hz), 5.17 (s, 2H), 5.38 (s, 2H), 5.96 (s, 2H), 6.61 (s, 1 H), 7.10 (dd, 1 H, J = 8.49, 1.65 Hz), 7.34-7.46 (m, 6H), 7.86 (s, 1 H), 9.71 (s, 1H). (stage 6) Production of N- (2-f6,6-dimethyl-1-f2- (trimethylsilyl) ethoxymethyl-4,5,6,7-tetrahydro-1 H -indazol-3-yl> -1-r2- (trimethylsilynetoxymethyl-) Benzyl 1H-indol-6-iO-N-methylcarbamate Under an argon atmosphere, to a solution of (2- {6,6-dimethyl-1- [2- (trimethylsilyl) ethoxymethyl] -4,5,6,7-tetrahydro-1 H-indazole-3- ## STR6 ## N -yl} -. -1 - [2- (trimethylsilyl) ethoxymethyl] -1H-indol-6-yl) benzyl carbamate (3 g, 4.6 mmol) in N, N-dimethylformamide (30 mL) was added sodium hydride ( 219 mg, 5.5 mmol) under cooling with ice and the mixture was stirred for 10 min. Then, methyl iodide (0.6 ml, 6.9 mmol) was added to the reaction mixture and the mixture was stirred for 3 h. To the reaction mixture were added ethyl acetate and water and the organic layer was separated. Then, the organic layer was washed successively with water and saturated brine and dried over sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel to give the title compound (2.2 g, 69% yield). 1 H-NMR (400MHz, DMSO-d 6) d: -0.21 (s, 9H), -0.03 (s, 9H), 0.66 (t, 2H, J = 8.01 Hz), 0.86 (t, 2H, J = 8.01 Hz ), 1.02 (s, 6H), 1.53 (t, 2H, J = 6.01 Hz), 2.49 (s, 2H), 2.60 (t, 2H, J = 6.01 Hz), 3.29 (s, 3H), 3.29 (t , 2H, J = 8.01), 3.59 (t, 2H, J = 8.01 Hz), 5.09 (s, 2H), 5.39 (s, 2H), 6.00 (s, 2H), 6.70 (s, 1 H), 7.03 (dd, H, J = 8.41, 2.00 Hz), 7.26-7.37 (m, 5H), 7.44-7.59 (m, 2H). (stage 7) Production of N- (2 ^ 6,6-dimethyl-1-y2- (trimethylsilyl) ethoxymethin-4,5,6,7-tetrahydro-1 H -indazol-3-ylV-1-r2- (trimethylsilyl) ethoxymethyl) n-1 H-indol-6-DN-methylamine A solution of N- (2- {6,6-dimethyl-1- [2- (trimethylsilyl) ethoxymethyl] -4,5,6,7-tetrahydro-1 H -indazol-3-yl}. 1- [2- (trimethylsilyl) ethoxymethyl] -1H-indol-6-yl) -N-methylcarbamate benzyl (2.2 g, 3.1 mmol), palladium on carbon 10% (216 mg) and ammonium formate (989 mg, 16 mmol) in ethanol (30 mL) was heated at reflux for 2.5 h. After cooling, the reaction mixture was filtered through celite and the filtrate was concentrated. The residue was purified by chromatography on silica gel to give the title compound (1.4 g, 79% yield). 1 H-NMR (400MHz, DMSO-d 6) d: -0.18 (s, 9H), -0.03 (s, 9H), 0. 69 (t, 2H, J = 8.41 Hz), 0.86 (t, 2H, J = 8.41 Hz), 1.01 (s, 6H), 1.52 (t, 2H, J = 6.41 Hz), 2.47 (s, 2H), 2.57 (t, 2H, J = 6.41 Hz), 2.73 (d, 3H, J = 5.21 Hz), 3.31 (t, 2H, J = 8.41), 3.58 (t, 2H, J = 8.41 Hz), 5.36 (s) , 2H), 5.50 (q, 1 H, J = 5.21 Hz), 5.94 (s, 2H), 6.42-6.55 (m, 3H), 7.25 (d, 1 H, J = 8.41 Hz). (stage 8) Production of N- [2- (6,6-dimethyl-4,5,6,7-tetrahydro-1 H -indazol-3-yl) -1 H -indol-6-yl-1-N-methylacetamide Under an argon atmosphere, to a solution of N- (2- {6,6-dimethyl-1- [2- (trimethylsilyl) ethoxymethyl] -4,5,6J-tetrahydro-1H-indazol-3-yl ) -1- [2- (trimethylsilyl) ethoxymethyl] -1H-indol-6-yl) -N-methylamine (100 mg, 0.18 mmol) and triethylamine (75 μ ?, 0.54 mmol) in chloroform (1.5 ml) were added acetyl chloride (19 μ ?, 0.27 mmol) at room temperature and the mixture was stirred for 2 h. Water was added to the reaction mixture and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed successively with water and saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure to give N- (2- {6,6-dimethyl-1- [2- (trimethylsilyl) ethoxymethyl] -4.5.6.7 -tetrahydro-1 H-indazol-3-yl.} -1- [2- (trimethylsilyl) ethoxymethyl] -1 H -indol-6-yl) -N-methylacetamide. A solution of N- (2- {6,6-dimethyl-1- [2- (trimethylsilyl) ethoxymethyl] -4,5,6,7-tetrahydro-1H-indazol-3-yl} -1- [2- (trimethylsilyl) ethoxymethyl] -1 H -indol -yl) -N-methylacetamide obtained in?,? -dimethylformamide (1.4 ml) was added to tetrabutylammonium fluoride ( 1.8 ml, 1.8 mmol) concentrated beforehand at reduced pressure. The ethylenediamine (0.7 ml) was added and the mixture was stirred with heating at 90 ° C for 24 h. After cooling, water and ethyl acetate were added and the organic layer was separated. Then, the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed successively with water and saturated brine and dried over sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel to give the title compound (26 mg, 42% yield).
EXAMPLE 2 Production of N-r2- (6,6-dimethyl-4,5,6,7-tetrahydro-1 H -indazol-3-iO-1 H-indol-6-ill-N-ethylacetamide) (stage 1) Production of N- (2-f6,6-dimethyl-1- [2- (tritymethylsilyl) ethoxymethyl-4.5.67-tetrahydric> -1 H -indazol-3-yl) -1-r2- (trimethylsilyl) ethoxymetill-1H-indo il) -N-ethylamine Under a nitrogen atmosphere, N- (2- {6,6-dimethyl-1- [2- (trimethylsilyl) ethoxymethylH, 5,6,7-tetrahydro-1H-indazol-3-yl} was obtained. -1- [2- (trimethylsilyl) ethoxymethyl] -1H-indol-6-yl) -N-ethylcarbamate benzyl in the same manner as in Example 1, Step 6, from (2-. {6 > 6-dimethyl-1- [2- (trimethylsilyl) ethoxymethyl] -4,5,6,7-tetrahydro-1 H -indazol-3-yl.] -1- [2- (trimethylsilyl) ethoxymethyl] - 1H-indol-6-yl) benzyl carbamate obtained in Example 1, Step 5. To a solution of N- (2- {6,6-d-methyl-1- [2- (tr ymethylsilyl) ethoxymethyl] -4,5,6,7-tetrahydro-1 H-indazol-3-yl.} - 1 - [2- (trimethylsilyl) ethoxymethyl] -1H-indol-6-yl) -N-ethylcarbamate benzyl obtained (979 mg, 1.4 mmol) in methanol (8 ml) was added 20% palladium hydroxide on carbon (400 mg). Then, the mixture was stirred under a hydrogen atmosphere at normal pressure for 1.5 h. After the reaction, the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel to give the title compound (802 mg, 100% yield). 1 H-NMR (400MHz, DMSO-d 6) d: -0.18 (s, 9H), -0.03 (s, 9H), 0.72 (t, 2H, J = 8.0 Hz), 0.89 (t, 2H, J = 8 Hz ), 1.05 (s, 6H), 1.21-1.24 (m, 3H), 1.52-1.57 (m, 2H), 2.50 (s, 2H), 2.56-2.64 (m, 2H), 3.10-3.13 (m, 2H) ), 3.32-3.36 (m, 2H), 3.61 (t, 2H, J = 8.0 Hz), 5.39 (s, 2H), 5.96 (s, 2H), 6.50 (s, 2H), 6.51-6.54 (m, 1 H), 6.61 (brs, 1H), 7.27 (d, 1 H, J = 8.0 Hz). (stage 2) Production of N-r2- (6.6-d¡meti, 5,6,7-tetrahydro-1 H -ndazol-3-yl) -1 H -indol-6-yl-1-N-ethylacetamide In the same manner as in Example 1, Step 8, the title compound (24 mg, 35% yield) was obtained from N- (2-. {6,6-dimethyl-1- [2- ( methylmethoxyethyl) -, 5,6,7-tetrahydro-1 H -ndazol-3-yl.} -1- [2- (tr ymethyl) l) ethoxymethyl] -1H-indol-6-yl) -N-ethylamine (110 mg, 0.19 mmol).
EXAMPLE 3 Production of N-. { 2- (6,6-dimethyl-4,5,6,7-tetrahydro-1 H-indazol-3-yO-1H-indol-6-yl) -N-methylcarbamate benzyl A solution of N- (2- {6,6-dimethyl-1- [2- (trimethylsilyl) ethoxymethyl] -4,5,6,7-tetrahydro-1 H -ndazol-3-yl.} .1 - [2- (Trimethylsilyl) ethoxymethyl] -1H-indol-6-yl) -N-methylcarbamate benzyl (13 g, 19 mmol) obtained in Example 1, Step 6, in N, N-dimethylformamide (102 ml) was added to tetrabutylammonium fluoride (93 ml, 93 mmol) concentrated beforehand under reduced pressure and then ethylene diamine (19 ml) was added. The mixture was stirred with heating at 90 ° C for 7 h. After cooling, water and ethyl acetate were added and the organic layer was separated. Then, the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed successively with water, 10% aqueous solution of citric acid and brine. saturated and dried over sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel to give the title compound (7.2 g, 91% yield).
EXAMPLE 4 Production of (S) -N-f2- (6,6-dimethyl-4,5,6,7-tetrahydro-1 H -indazol-3-yl) -1 H -indole-6-in-N-methyl-2- (morpholine) -4-il) propionamide (stage 1) Production of N-r2- (6.6-dimethyl-4.5.6.7-tetrahydro-1 H-indazol-3-yl) -1 H -indole-6-in-N-methylamine Under a nitrogen atmosphere, to a solution of N-. { 2- (6,6-Dimeti, 5,67-tetrahydro-1 H -indazol-3-yl) -1H-indol-6-yl} -N-methylcarbamate obtained in Example 3 (7.2 g, 17 mmol) in ethanol (72 ml) were added 10% palladium on charcoal (723 mg) and ammonium formate (2.5 g, 39 mmol) and the mixture it was stirred with heating at 65 ° C for 40 min.
After cooling, the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was washed in suspension in water (300 ml). The precipitate was collected by filtration, washed with water and dried under reduced pressure to give the title compound (4.5 g, 90% yield). 1 H-NMR (400MHz, DMSO-d 6) d: 1.00 (s, 6H), 1.56 (t, 2H, J = 6.41 Hz), 2.38 (s, 2H), 2.61 (t, 2H, J = 6.41 Hz), 2.69 (d, 3H, J = 4.81 Hz), 5.24-5.34 (m, 1 H), 6.33-6.46 (m, 3H), 7.18 (d, 1 H, J = 8.41 Hz), 10.65 (s, 1 H) ), 12.28 (s, 1 H). (stage 2) Production of (S) -N-r2- (6,6-dimethyl-4,5,6,7-tetrahydrc-1 H -indazol-3-yl) -1 H -indole-6-in-N-methyl-2- (morpholine) -4-il) propionamide To a solution of N-. { 2- (6,6-Dimeti, 5,6,7-tetrahydro-1 H -indazol-3-yl) -1 H -indole-6-yl} -N-methylamine (45 mg, 0.15 mmol) in pyridine (1 mL) was added (S) -2- (morpholin-4-yl) propionic acid obtained in Reference Example 3 (110 mg, 0.69 mmol) and hydrochloride of 1- ethyl-3- (3-dimethylaminopropyl) carbodiimide (106 mg, 0.55 mmol) at room temperature and the mixture was stirred for 14 h. Chloroform and water were added to the reaction mixture and the organic layer was separated. The organic layer was dried over sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was then dissolved in a mixed solvent of tetrahydrofuran (1 ml) and methanol (1 ml). To the solution was added 2 N aqueous solution of sodium hydroxide (0.35 ml) at room temperature and the mixture was stirred for 20 min. Chloroform and water were added to the reaction mixture and the organic layer was separated. The organic layer was dried over sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel to give the title compound (52 mg, 78% yield).
EXAMPLE 5 Production of (S) -N-r2- (6,6-dimethyl ^ 4.5.6.7-tetrahydro-1H-indazol-3-yl) -1 H -indole-6-in-N-methyl-2-hydrochloride ( morpholin-4-yl) propionamide To a solution of (S) -N- [2- (6,6-dimeti, 5,6,7-tetrahydro-1 H- -3-yl) -1 H -indol-6-yl] -N-methyl -2- (morpholin-4-yl) propionamide obtained in Example 4 (100 mg, 0.23 mmol) in ethyl acetate (1 mL) was added 4 N hydrochloric acid / ethyl acetate (0.06 mL, 0.24 mmol) at room temperature and the mixture was stirred for 30 min. The precipitated crystals were collected by filtration, washed with ethyl acetate and dried under reduced pressure to give the title compound (75 mg, 69%).
EXAMPLE 6 Production of N-r2- (6.6-dimethyl-4.5.6.7-tetrahydro-1 H -indazol-3-yl) -1 H-indol-6-in-N-methyl-2- (3-oxomorpholin-4-yl) acetamide Under an argon atmosphere, to a solution of N- [2- (6,6-dimeti, 5,6,7-tetrahydro-1 H -indazol-3-yl) -1H-indol-6-yl] - N-methylamine obtained in Example 4, Step 1 (40 mg, 0.14 mmol) and (3-oxomorpholin-4-yl) acetic acid obtained in Reference Example 4 (76 mg, 0.48 mmol) in pyridine (1.3 ml) 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (91 mg, 0.48 mmol) was added at room temperature and the mixture was stirred at room temperature for 12 h. Then, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (1.2 ml), the 2 N aqueous solution of sodium hydroxide (1.0 ml) was added and the mixture was stirred at room temperature for 45 min. Then, water and ethyl acetate were added to the reaction mixture and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were washed successively with water and saturated brine and dried over sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel to give the title compound (40 mg, 67% yield).
EXAMPLE 7 Production of 2- (6,6-dimethyl-4,5,6,7-tetrahydro-1 H-indazol-3-yl) -1 H-indole-6-carboxylic acid (2-hydroxy-1-methylethyl) methylamide (stage 1) Production of 2- (6,6-dimethyl-1-f2- (trimethylsilyl) ethoxymethyl-1-6.6.6.7-tetrahydro-1 H-indazol-3-yl) -2- (6,6-dimethyl-1-f2-yl) -2-hydroxy-1-methylethyl-amide -r2- (trimethylsihl) ethoxymethyl-H-indole-6-carboxylic acid To a solution of acid 2-. { 6,6-dimethyl-1- [2- (trimethylsilyl) ethoxymethylH, 5,6,7-tetrahydro-1 H -indazol-3-yl} -1- [2- (Trimethylsilyl) ethoxymethyl] -1H-indole-6-carboxylic acid obtained in Example 1, Step 4 (500 mg, 0.88 mmol) in N, N-dimethylformamide (5 mL) were added 1-hydroxybenzotriazole monohydrate (161 mg, 1.1 mmol), 1- ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (202 mg, 1.1 mmol) and 2-amino-1-propanol (84 mg, 1.1 mmol) a Room temperature and the mixture was stirred at room temperature for 7 h. Water and ethyl acetate were added to the reaction mixture and the organic layer was separated. Then, the organic layer was washed successively with water and saturated brine and dried over sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel to give the title compound (511 mg, yield 93%). 1 H-NMR (400MHz, DMSO-d 6) d: -0.22 (s, 9H), -0.03 (s, 9H), 0.68 (t, 2H, J = 8.12 Hz), 0.87 (t, 2H, J = 8.12 Hz ), 1.03 (s, 6H), 1.17 (d, 3H, J = 6.72 Hz), 1.54 (t, 2H, J = 6.26 Hz), 2.50 (s, 2H), 2.62 (t, 2H, J = 6.26 Hz) ), 3.29 (t, 2H, J = 8.12 Hz), 3.35-3.39 (m, 1 H), 3.48-3.53 (m, 1 H), 3.60 (t, 2H, J = 8.12 Hz), 4.01-4.11 ( m, 1 H), 4.74 (t, 1 H, J = 5.68 Hz), 5.41 (s, 2H), 6.11 (s, 2H), 6.76 (s, 1 H), 7.57-7.67 (m, 2H), 8.01 (d, 1 H, J = 7.88 Hz), 8.15 (s, 1 H). (stage 2) Production of f2- (tert-butyldiphenylsilyloxy) -1-methylethylamide of 2 ^ 6.6 ^ imetyl-1-f2- (trimethylsilyl) ethoxymethyl .5.6.7-tetrahydro-1 H -indazol-3-yl-1- G2- ( trimethylsilyl) ethoxymethyl-1 H- indol-6-carboxylic acid To a solution of 2- (2-hydroxy-1-methylethyl) -amide. { 6,6-Dimethyl-1- [2- (trimethylsilyl) ethoxymethyl] ^, 5,6,7-te ^^ (trimethylsilyl) ethoxymethyl] -1H-indole-6-carboxylic acid (265 mg, 0.42 mmol) in N, N-dimethylformamide (2.7 ml) were added imidazole (35 mg, 0.51 mmol) and tert-butyldiphenylsilyl chloride (132 μ) ,, 0.51 mmol) under cooling with ice and the mixture was stirred at room temperature for 8 h. Then, water and ethyl acetate were added to the reaction mixture and the organic layer was separated. Then, the organic layer was washed successively with water and saturated brine and dried over sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel to give the title compound (341 mg, yield 93%).
H-NMR (400MHz, DMSO-d6) d: -0.24 (s, 9H), -0.03 (s, 9H), 0.64 (t, 2H, J = 8.12 Hz), 0.87 (t, 2H, J = 8.12 Hz ), 1.00 (s, 9H), 1.02 (s, 6H), 1.26 (d, 3H, J = 6.96 Hz), 1.53 (t, 2H, J = 6.38 Hz), 2.50 (s, 2H), 2.60-2.65 (m, 2H), 3.24-3.28 (m, 5H), 3.55-3.65 (m, 3H), 3.70-3.77 (m, 1 H), 4.23 ^ .34 (m, 1 H), 5.41 (s, 2H) ), 6.09 (s, 2H), 6.76 (s, 1 H), 7.36-7.47 (m, 6H), 7.58-7.67 (m, 6H), 8.10-8.16 (m, 2H). (stage 3) Production of 2-j6,6-dimethyl-1- [2- (trimethylsilyl) ethoxymethyl] -4,5,6,7-tetrahydro-1 H-indazole-3- (tert-butyldiphenylsilyloxy) -1-methylethyl-1-methylamide il > - 1-G2- (trimethylsilyl) ethoxymethyl-1 H- indol-6-carboxylic Under an argon atmosphere, to a solution of 2- (tert-butyldiphenylsilyloxy) -1-methylethyl] -amide. { 6,6-dimethyl-1- [2- (trimethylsilyl) ethoxymethylene] -, 5,6,7-tetrahydro-1 H -indazol-3-yl} 1- [2- (trimethylsilyl) ethoxymethyl] -1 H -indole-6-carboxylic acid (337 mg, 0.39 mmol) in N, N- dimethylformamide (3.4 mL) were added sodium hydride (19 mg, 0.47 mmol) and methyl iodide (36 μ ?, 0.58 mmol) under ice-cooling and the mixture was stirred at room temperature for 3 h. Water and ethyl acetate were added to the reaction mixture and the organic layer was separated. Then, the organic layer was washed successively with water and saturated brine and dried over sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel to give the title compound (149 mg, 44% yield). 1 H-NMR (400MHz, DMSO-d 6) d: -0.23 (s, 9H), -0.05 (s, 9H), 0. 59-0.62 (br m, 2H), 0.86 (dd, 2H, J = 10.44, 5.80 Hz), 0.98 (s, 9H), 1.02 (s, 6H), 1.08 (br s, 3H), 1.54 ( t, 2H, J = 6.26 Hz), 2.50 (s, 2H), 2.61-2.64 (br m, 2H), 2.83 (s, 3H), 3.21-3.29 (m, 2H), 3.38-3.46 (m, 0.6 H), 3.54-3.83 (m, 1.4H), 3.58 (t, 2H, J = 8.00 Hz), 4.04-4.17 (m, 0.6H), 4.72-4.90 (brm, 0.4H), 5.39-5.41 ( br m, 2H), 5.69-5.83 (m, 0.6H), 5.96-6.09 (m, 1.4H), 6.77 (s, 1 H), 7.1 1 (d, 1 H, J = 9.04 Hz), 7.17- 7.75 (m, 12H). (stage 4) Production of 2- (6.6 ^ imeti, 5,6,7-tetrahydro-1H-indazol-3-yl) -1H-indole-6-carboxylic acid (2-hydroxy-1-methylethyl) methylamide A solution of 2 ^ 6I6 ^ imetyl-1- [2- (trirnethylsilyl) ethoxymethyl] -4l5,6,7-tetrahydro-1 H-indazole-2 [2- (tert-butyldiphenylsilyloxy) -1-methylethyl] methylamide. -il} -1- [2- (Trimethylsilyl) ethoxymethyl] -1H-indole-6-carboxylic acid (145 mg, 0.17 mmol) in N, N-dimethylformamide (1.2 mL) was added to tetrabutylammonium fluoride (1.7 mL, 1.7 mmol) concentrated prior to reduced pressure. The ethylenediamine (0.29 ml) was added and the mixture was stirred with heating at 90 ° C for 14 h. After cooling, water and ethyl acetate were added to the mixture and the organic layer was separated, washed successively with water, 10% aqueous solution of citric acid and saturated brine and dried over sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel to give the title compound (57 mg, 90% yield).
EXAMPLE 8 Production of N-r2- (6-hydroxymethyl-6-methyl-4.5.6J-tetrahydro-1H-indazol-3-yl) -1H-indol-6-in-N-methyl-2- (2-oxopiperidin- 1-il) acetamide (stage 1) Production of N- (2-. {6-benzyloxymethyl-6-methyl-1- [2- (trimethylsilyl) ethoxymethyl-1, 5,6,7-tetrahydro-1 H -indazol-3-yl) -1- [2- (trimethylsilyl) ethoxymethyl-1 H- indol-6-yl) - N -methylamine In the same manner as in Example 1, step 7, the title compound was obtained from 6-benzyloxymethyl-3-iodo-6-methyl-4,5,6,7-tetrahydroindazole-1-carboxylate ter- butyl obtained in Reference Example 5 and 2-boronylindole-1,6-dicarboxylic acid-1-tert-butyl-6-methyl ester obtained in Reference Example 2. (stage 2) Production of N- (2-f6-hydroxymethyl-6-methyl-1- [2- (trimethylsilyl) ethoxymethyl-4,5,6,7-tetrahydro-1 H -indazol-3-yl> -1-r2- (trimethylsilyl) ethoxymethin-1 H-indol-6-yl) -N-methyl-2- (2-oxopiperidin-1-D-acetamide) To a solution of N- (2- {6-benzyloxymethyl-6-methyl-1- [2- (trimethylsilyl) ethoxymethyl] -4,5,6,7-tetrahydro-1H-indazol-3-yl}. -1- [2- (trimethylsilyl) ethoxymethyl] -1 H -indole-6-yl) -N-methylamine (150 mg, 0.23 mmol) in N, N-dimethylformamide (3 mL) were added (2- oxopiperidin-1-yl) acetic obtained in Reference Example 6 (43 mg, 0.27 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (52 mg, 0.27 mmol) and 1-hydroxybenzotriazole monohydrate (37 mg, 0.27 mmol) and the mixture was stirred at room temperature overnight. To the reaction mixture were added ethyl acetate and water and the organic layer was separated, washed successively with water and saturated brine and dried over sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel to give N- (2- {6-benzyloxymethyl-6-methyl-1- [2- (trimethylsilyl) ethoxymethyl] -, 5,6,7-tetrahydro-1 H -indazol-3-yl) -1- [2- (trimethylsilyl) ethoxymethyl] -1 H -indol-6-yl) -N-methyl-2- (2-oxopiperidin-1-yl) acetamide (158 mg). Under a nitrogen atmosphere, to a solution of N- (2- {6-benzyloxymethyl-6-methyl-1- [2- (trimethylsilyl) ethoxymethyl] -4,5,6,7-tetrahydro-1 H -indazol-3-yl.}. -1- [2- (trimethylsilyl) ethoxymethyl] -1H-indol-6-yl) -N-methyl-2- (2-oxopiperidin-1-yl) acetamide obtained (158 mg) in a mixed solvent of methanol (0.8 ml) and tetrahydrofuran (0.8 ml) was added 20% palladium hydroxide on carbon (150 mg) at room temperature and the mixture was stirred under a hydrogen atmosphere at normal pressure for 4 hours. h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give the title compound (120 mg, 75% yield). 1 H-NMR (400MHz, DMSO-d 6) d: -0.21 (9H, s), -0.04 (9H, s), 0.67 (2H, t, J = 7.86 Hz), 0.86 (2H, t, J = 8.06 Hz ), 0.93 (3H, s), 1.44-1.73 (6H, m), 2.12-2.21 (2H, m), 2.39 (1 H, d, J = 16.52 Hz), 2.59-2.65 (2H, m), 2.59 (1 H, d, J = 16.52 Hz), 3.22 (3H, s), 3.27 (2H, s), 3.31 (2H, t, J = 8.06 Hz), 3.59 (2H, t, J = 7.86 Hz), 3.81 (2H, s), 4.71 (1H, t, J = 5.44 Hz), 5.38 (1H, d, J = 11.28 Hz), 5.41 (1H, d, J = 11.69 Hz), 6.02 (1H, d, J = 10.48 Hz), 6.07 (1 H, d, J = 10.88 Hz), 6.74 (1 H, s), 7.06 (1 H, d, J = 7.66 Hz), 7.60 (1 H, s), 7.64 (1 H , d, J = 8.06 Hz). (stage 3) Production of N- [2- (6-hydroxymethyl-6-methyl-4,5,6,7-tetrahydro-1 H -indazol-3-yl) -1 H -indol-6-ill-N-methyl-2- (2- oxopiperidin-1-yl) acetamide A solution of N- (2-. {6-hydroxymethyl-6-methyl-1- [2- (trimethylsilyl) ethoxymethyl, 5,6,7-tetrahydro-1 H -indazol-3-yl.} -1 - [2- (trimethylsilyl) ethoxymethyl] -1H-indol-6-yl) -N-methyl-2- (2-oxopiperidin-1-yl) acetamide (63 mg, 0.09 mmol) in N, N-dimethylformamide ( 1.5 ml) was added to concentrated tetrabutylammonium fluoride (0.6 ml, 0.6 mmol) beforehand under reduced pressure. Ethylenediamine (0.2 ml) was added and the mixture was stirred with heating at 80 ° C overnight. After cooling, water and ethyl acetate were added and the organic layer was separated. Then, the organic layer was washed successively with water and saturated brine and dried over sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on thin layer of silica gel to give the title compound (5.5 mg, yield 16%).
The compounds of Examples 9-381 were obtained in the same manner as in the aforementioned examples. The structural formulas and their data of the 1H-NMR spectra are shown in Tables 1-1 to 1-78.
In the tables, the compounds in an optically active form are indicated with (an optically active form) in Example Number.
The 1 H-NMR spectra were measured in CDCI3 or DMSO-D6, with tetramethylsilane as an internal standard and all d values are shown in ppm. Unless otherwise specifically indicated in the Table, the resolution capability was measured at 400 MHz.
The symbols in the boxes mean the following, s: singlet d: doublet t: triplet q: quartet dd: double double ddd: double double double brs: wide singlet m: multiplote J: coupling constant TABLE 1-1 TABLE 1-2 TABLE 1-3 TABLE 1-4 TABLE 1-5 TABLE 1-6 TABLE 1-7 TABLE 1-8 TABLE 1-9 TABLE 1-10 TABLE 1-11 TABLE 1-13 TABLE 1-14 TABLE 1-15 TABLE 1-16 TABLE 1-17 TABLE 1-18 TABLE 1-19 TABLE 1-20 TABLE 1-21 TABLE 1-22 TABLE 1-24 TABLE 1-25 TABLE 1-26 TABLE 1-27 TABLE 1-29 TABLE 1-30 TABLE 1-31 TABLE 1-32 TABLE 1-33 TABLE 1-35 TABLE 1-36 TABLE 1-37 TABLE 1-38 TABLE 1-39 TABLE 1-40 TABLE 1-41 TABLE 1-42 TABLE 1-43 TABLE 1-44 twenty TABLE 1-45 TABLE 1-46 TABLE 1-47 TABLE 1-48 TABLE 1-49 TABLE 1-50 TABLE 1-51 TABLE 1-52 TABLE 1-53 TABLE 1-54 TABLE 1-55 TABLE 1-56 TABLE 1-57 TABLE 1-58 10 twenty TABLE 1-59 fifteen 20 TABLE 1-60 TABLE 1-61 TABLE 1-62 TABLE 1-63 TABLE 1-65 TABLE 1-66 TABLE 1-68 TABLE 1-69 TABLE 1-70 TABLE 1-71 TABLE 1-74 TABLE 1-75 TABLE 1-76 TABLE 1-77 TABLE 1-78 EXPERIMENTAL EXAMPLE Inhibitory activity of ITK (1) Preparation of the hITK enzyme The hITK enzyme was prepared by strong expression of the FLAG-labeled full length ITK in the Sf9 cells, and purification of these with an anti-FLAG antibody column. (2) Preparation of biotinylated GST-SLP76 The biotinylated GST-SLP76 was prepared by the strong expression of SLP76 labeled with GST (aa95-175) in Escherichia coli, the purification of these by glutathione sepharose column and the biotinylation of these. (3) Preparation of the solution (i) buffer for dilution: 20 mmol / L of 3- (N-morpholino) propanesulfonic acid (pH 7.0) (DOJINDO LABORATORIES), 10 mmol / L of magnesium chloride (Sigma-Aldrich Corporation), 1 mmol / L of dithiothreitol (Nacalai Tesque, Inc.), 0.1% gelatin (Sigma-Aldrich Corporation) (ii) substrate solution: 0.2 μg / mL of biotinylated GST-SLP76, 100 μ? t ??? _ of ATP (Sigma-Aldrich Corporation), prepared with buffer for dilution (iii) solution of the test compound: test compound, 50% dimethylsulfoxide (DMSO), prepared with buffer for dilution (iv) enzyme solution: 50 ng / mL of hITK enzyme, prepared with buffer for dilution (v) control solution: solution after extraction of the test compound from the mixture of the aforementioned (i), (ii) and (iii) (vi) white solution: solution after extraction of ATP from the mixture of the aforementioned (i), (ii) and (iii) (vii) detection buffer: 0.1 μ? ^? of anti-phosphotyrosine (PT66) -criptato (Cisbio), 2.5 μgglL · of XL665 binding to streptavidin (Cisbio), 50 mmol / L of 4- (2-hydroxyethyl) -1-piperazinetansulfonic acid (pH 7.4) (Nacalai Tesque, Inc.), 30 mmol / L of EDTA (NipponGene), 0.1% of TritonX ( Sigma-Aldrich Corporation), 200 mmol / L of potassium fluoride (Wako Puré Chemical Industries, Ltd.), 0.05% of bovine serum albumin (Sigma-Aldrich Corporation) (4) Measurement of inhibitory activity ITK A substrate solution (25 μL / well), a test compound solution (5 μL / well) and an enzyme solution (20 μL / well) were added to a 96-well medium-area white plate (plate , Corning Incorporated 3642) to begin a kinase reaction. The plate was parked at room temperature for 10 minutes. minutes Then, a detection buffer (50 μ? _ / ????) was added to the plate. After 2 hours of the addition of the detection buffer, the fluorescence intensity was measured at 620 nm (excited at 337 nm), and the fluorescence intensity at 665 nm (excited at 620 nm) was measured with a fluorescence microplate reader.
The Ratio (fluorescence intensity at 665 nm / fluorescence intensity at 620 nm x 10000) of each test compound was calculated from the measured fluorescence intensity. Simultaneously, the measurement was made using a blank solution and a control solution and the% control value of each test compound was calculated from the following formula.
Control% = (Ratio of test compound - Target ratio) / (ratio of control-target ratio)? 100 Inhibitory rate of ITK (%) = 100 - (% of control) The IC50 value was calculated from the concentrations of the test compound in points between 50% of the ITK inhibitory rate. The results are shown in Table 2 in values of nM. The numerical value in% of the Table shows the inhibitory rate of ITK (%) in the concentration indicated in parentheses.
TABLE 2-1 TABLE 2-2 TABLE 2-3 TABLE 2-4 TABLE 2-5 TABLE 2-6 TABLE 2-7 TABLE 2-8 In the assay of the compounds of Examples 380 and 381, the ATP concentration of the substrate solutions was 6 μ ???? / L From the above results, it is clear that the compound of the present invention has an inhibitory action of ITK.
Formulation example 1 (production of capsules) 1) compound of Example 1 30 mg 2) microcrystalline cellulose 10 mg 3) lactose 19 mg 4) magnesium stearate 1 mg 1), 2), 3) and 4) are mixed and packed in a gelatin capsule.
Formulation example 2 (tablet production) 1) compound of Example 1 10 g 2) lactose 50 g 3) corn starch 15 g 4) Carmellose calcium 44 g 5) magnesium stearate 1 g The complete quantities of 1), 2) and 3) and 30 g of 4) are kneaded with water, dried under vacuum and sieved. The sieved powder is mixed with 14 g of 4) and 1 g of 5) and the mixture is compressed with a tabletting machine. In this way, 1000 tablets each containing 0 mg of the compound of Example 1 are obtained per tablet.
Industrial Applicability Thus, the indole compound of the present invention can be an effective medicament for the treatment or prevention of inflammatory diseases, allergic diseases, autoimmune diseases, rejection to transplantation and the like.
This application is based on a patent application No. Application 2009-268040 filed in Japan, the content of which is fully incorporated herein.

Claims (26)

NOVELTY OF THE INVENTION CLAIMS
1 .- A compound represented by the following formula [I] one of its pharmaceutically acceptable salts: wherein R1 is (1) a hydrogen atom, (2) a hydroxy group, or (3) a C-i6 alkoxy group optionally substituted with aryl groups? e-??? R2 and R3 are the same or different and each is (1) a hydrogen atom, or (2) a Ci_6 alkyl group optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group and (b) an alkoxy group Ci_6 And R4 is a group represented by which is attached to the 5-position or the 6-position of the indole ring, wherein R5 is (1) a hydrogen atom, or (2) a Ci_6 alkyl group, and R6 is (1) a hydrogen atom, (2) a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a C 1-6 alkoxy group (c) a carboxy group, (d) a C 1 e-carbonyl alkoxy group, (e) an aryl group Ce-10, (f) an aryl C6-io-oxy group, (g) an amino group optionally mono- or disubstituted with Ci_6 alkyl groups, (h) a 5 or 6 membered unsaturated heterocyclic group optionally substituted with Ci_6 alkyl groups and (i) a saturated 5- or 6-membered heterocyclic group, (3) a C-i_6 alkoxy group, (4) a C6-io aryl group, or (5) an unsaturated heterocyclic group of 5 or 6 members optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group and (b) an alkoxy group or R5 and R5 form, together with the nitrogen atom to which they are attached, a cyclic amine of 5 or 6 m Members (said cyclic amine is optionally condensed with 5 or 6 membered unsaturated heterocycle) optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a Ci_6 alkyl group, (c) an alkoxy group Ci_e y ( d) a Ci_6-carbonyl alkoxy group; R7 is (1) a hydrogen atom, or (2) a Ci_6 alkyl group optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a Ci_6 alkoxy group and (c) an optionally mono amino group - or disubstituted with Ci_6 alkyl groups, and R8 is (1) a Ci_6 alkyl group optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a Ci_6 alkoxy group optionally substituted with aryl groups C6-io > (c) a C3_cycloalkyl group optionally substituted with Ci_6 alkoxy groups, (d) a C6-io aryl group, (e) an unsaturated heterocyclic group of 5 or 6 members optionally substituted with oxo groups, (f) a saturated 5- to 8-membered heterocyclic group optionally substituted with 1 to 3 substituents selected from (i) a hydroxy group, (ii) a Ci_6 alkyl group optionally substituted with 1 to 3 selected substituents of a hydroxy group and an alkoxy group Cie, (iii) an alkoxy group and (iv) an oxo group, (g) a C3_6-oxy cycloalkyl group, (h) an aryl C6-io-oxy group, (i) a unsaturated 5 or 6 membered heterocyclyloxy group, (j) a saturated 5- or 6-membered heterocyclyloxy group and (k) an optionally mono- or disubstituted amino group with substituents selected from (i) a Ci_5 alkyl group optionally substituted with 1 to 3 substituents selected from a hydroxy group, a carboxy group and a Ci_6 carboxy-alkoxy group, (ü) a Cis-carbonyl alkyl group optionally substituted with 1 to 3 substituents selected from a hydroxy group and an Ci_6 alkoxy group, (iii) ) a Ci_6-carbonyl alkoxy group optionally substituted with C6-io aryl groups, and (iv) a C3_s-carbonyl cycloalkyl group optionally substituted with C2 alkoxy groups, (2) a Ci_6 alkoxy group optionally substituted with C6-io aryl groups, (3) a C3_6 cycloalkyl group optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group and (b) a Ci_6 alkoxy group, (4) a C6-10 aryl group optionally substituted with Ci_6 alkyl groups optionally substituted with 1 to 3 halogen atoms, (5) ) an optionally mono- or di-substituted amino group with alkyl groups optionally substituted with C6-io aryl groups, (6) a 5- or 6-membered unsaturated heterocyclic group optionally substituted with Ci_6 alkyl groups, (7) a saturated 5- or 6-membered heterocyclic group optionally substituted with 1 to 3 substituents selected from (a) an alkyl group Ci_6l (b) a Ci_6-carbonyl alkyl group and (c) a group oxo, (8) a C3_6-oxi cycloalkyl group, or (9) an aryl C6-io-carbonyl group or R7 and R8 form, together with the nitrogen atom and the carbon atom to which they are attached, a cyclic amine of 5 or 6 members substituted with an oxo group and also optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a C-i_6 alkyl group optionally substituted with hydroxy groups, (c) a Ci_6 alkoxy group and (d) a C3_6 cycloalkyl group.
2. - A compound represented by the following formula [1-a] or a pharmaceutically acceptable salt thereof: wherein R is (1) a hydrogen atom, (2) a hydroxy group, or (3) a Ci_6 alkoxy group optionally substituted with aryl groups Ce-??; R2 and R3 are the same or different and each is (1) a hydrogen atom, or (2) an Ci_s alkyl group optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group and (b) an Ci_6 alkoxy group R7 'is a Ci_6 alkyl group optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a Ci-6 alkoxy group and (c) an amino group optionally mono- or disubstituted with Ci_6 alkyl groups, and R8 is (1) a Ci_6 alkyl group optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a Ci_6 alkoxy group optionally substituted with aryl groups Ce - ??, (c) a C3_6 cycloalkyl group optionally substituted with Ci_e alkoxy groups, (d) an aryl group Ce - 0, (e) a 5 or 6 membered unsaturated heterocyclic group optionally substituted with oxo groups, (f) a saturated 5- to 8-membered heterocyclic group optionally substituted with 1 to 3 substituents selected from (i) a hydroxy group, ( ii) a C1-6 alkyl group optionally substituted with 1 to 3 substituents selected from a hydroxy group and a Ci_6 alkoxy group, (iii) a Ci_6 alkoxy group and (iv) an oxo group, (g) a C3_6 cycloalkyl group oxy, (h) an aryl group C6-io-oxi, (i) an unsaturated 5 or 6-membered heterocyclyloxy group, ( j) a saturated 5- or 6-membered heterocyclyloxy group and (k) an amino group optionally mono- or disubstituted with substituents selected from (i) a Ci_6 alkyl group optionally substituted with 1 to 3 substituents selected from a hydroxy group, a carboxy group and a Ci_6 carboxy-alkoxy group, (ii) a Ci_6-carbonyl alkyl group optionally substituted with 1 to 3 substituents selected from a hydroxy group and a C-i_6 alkoxy group, (iii) a Ci_6-carbonyl alkoxy group optionally substituted with groups aryl C6-io and (iv) a C3_6-carbonyl cycloalkyl group optionally substituted with Ci_6 alkoxy groups, (2) a Ci_6 alkoxy group optionally substituted by aryl groups Ce -,, (3) an optionally substituted C3-6 cycloalkyl group with 1 to 3 substituents selected from (a) a hydroxy group and (b) a Ci_6 alkoxy group, (4) a C6-io aryl group optionally substituted with Ci_6 alkyl groups optionally substituted with 1 to 3 halogen atoms, (5) an amino group or optionally mono- or di-substituted with Ci_6 alkyl groups optionally substituted with C6-10 aryl groups, (6) a 5- or 6-membered unsaturated heterocyclic group optionally substituted with Ci_6 alkyl groups, (7) a saturated 5- or 6-membered heterocyclic group optionally substituted with 1 to 3 substituents selected from (a) a C 1-6 alkyl group, (b) a C 1-6 alkylcarbonyl group and (c) an oxo group, (8) a C 3-6 cycloalkyl-oi group, or (9) ) an aryl C6-io-carbonyl group or R7 and R8 form, together with the nitrogen atom and the carbon atom to which they are attached, a cyclic amine of 5 or 6 members substituted with an oxo group and also optionally substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a C 1-6 alkyl group optionally substituted with hydroxy groups, (c) a C 1-6 alkoxy group and (d) a C 3-6 cycloalkyl group.
3. - The compound according to claim 2, further characterized in that R is a hydrogen atom; and R2 and R3 are the same or different and each is a Ci_6 alkyl group, or a pharmaceutically acceptable salt thereof.
4. - The compound according to claim 3, further characterized in that R7 is a Ci_6 alkyl group; and R8 is a Ci_6 alkyl group substituted with 1 to 3 substituents selected from (a) a hydroxy group, (b) a C1-6 alkoxy group optionally substituted with C6-io aryl groups > (c) a C3_6 cycloalkyl group optionally substituted with C1-6 alkoxy groups, (d) an aryl group C6-io > (e) a 5 or 6 membered unsaturated heterocyclic group optionally substituted with oxo groups, (f) a saturated 5- to 8-membered heterocyclic group optionally substituted with 1 to 3 substituents selected from (i) a hydroxy group, (ii) a Ci_6 alkyl group optionally substituted with 1 to 3 substituents selected from a hydroxy group and a C 1 alkoxy group, (i) a Ci_6 alkoxy group and (iv) an oxo group, (g) a C3_6-oxy cycloalkyl group, (h) an aryl Ce-io-oxy group, (i) a 5 or 6 membered unsaturated heterocyclyloxy group, (j) a saturated 5- or 6-membered heterocyclyloxy group and (k) an optionally mono- or di-substituted amino group with substituents selected from (i) a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from a hydroxy group, a carboxy group and a C 1-6 carboxy-alkoxy group, (ii) a C 1 -carbonyl alkyl group optionally substituted with 1 to 3 substituents selected from a hydroxy group and a Ci_6 alkoxy group, (iii) a C 1 -carbonyl alkoxy group optionally substituted with C 6 -aryl aryl groups and (iv) a C 3-6 cycloalkyl-carbonyl group optionally substituted with C 1-6 alkoxy groups, or a pharmaceutically acceptable salt thereof.
5. - A compound selected from the following formulas 363 of its pharmaceutically acceptable salts.
6. - A pharmaceutical composition comprising a compound of any of claims 1 to 5 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
7. - An ITK inhibitor comprising the compound of any of claims 1 to 5 or a pharmaceutically acceptable salt thereof.
8. An agent for the treatment or prevention of an inflammatory disease, comprising the compound of any of claims 1 to 5 or a pharmaceutically acceptable salt thereof.
9. - The agent according to claim 8, further characterized in that the inflammatory disease is rheumatoid arthritis.
10. - An agent for the treatment or prevention of an allergic disease, comprising the compound of any of claims 1 to 5 or a pharmaceutically acceptable salt thereof.
1. An agent for the treatment or prevention of an autoimmune disease, comprising the compound of any of claims 1 to 5 or a pharmaceutically acceptable salt thereof.
12. - The agent according to claim 1, further characterized in that the autoimmune disease is rheumatoid arthritis.
13. - An inhibitor of rejection to transplantation, comprising the compound of any of claims 1 to 5 or a pharmaceutically acceptable salt thereof.
14. - A method of inhibiting ITK in a mammal, comprising administering a pharmaceutically effective amount of the compound of any of claims 1 to 5 or a pharmaceutically acceptable salt thereof, to the mammal.
15. - A method of treating or preventing an inflammatory disease in a mammal, comprising administering a pharmaceutically effective amount of the compound of any of claims 1 to 5 or a pharmaceutically acceptable salt thereof, to the mammal.
16. - The method according to claim 15, further characterized in that the inflammatory disease is rheumatoid arthritis.
17. A method of treating or preventing an allergic disease in a mammal, comprising administering a pharmaceutically effective amount of the compound of any of claims 1 to 5 or a pharmaceutically acceptable salt thereof, to the mammal.
18. - A method of treatment or prevention of an autoimmune disease to a mammal, comprising the administration of a pharmaceutically effective amount of the compound of any of claims 1 to 5 or a pharmaceutically acceptable salt thereof, to the mammal.
19. - The method according to claim 18, further characterized in that the autoimmune disease is rheumatoid arthritis.
20. - A method of suppressing rejection to transplantation in a mammal, comprising administering a pharmaceutically effective amount of the compound of any of claims 1 to 5 or a pharmaceutically acceptable salt thereof, to the mammal.
21. The use of the compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, to produce a medicament for the treatment or prevention of an inflammatory disease.
22. - The use as claimed in claim 21, wherein the inflammatory disease is rheumatoid arthritis.
23. - The use of the compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, to produce a medicament for the treatment or prevention of an allergic disease.
24. - The use of the compound of any of claims 1 to 5 or a pharmaceutically acceptable salt thereof, to produce a medicament for the treatment or prevention of an autoimmune disease.
25. - The use as claimed in claim 24, wherein the autoimmune disease is rheumatoid arthritis.
26. The use of the compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, to produce a medicament for suppressing rejection to transplantation.
MX2012006017A 2009-11-25 2010-11-25 Indole compound and pharmaceutical use thereof. MX2012006017A (en)

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